Inflammasomes and Their Roles in Health and

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ANNUAL REVIEWS

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Annu. Rev. Cell Dev. Biol. 2012.28:137-161. Downloaded from www.annualreviews.org by F. Hoffmann-La Roche Ltd. on 02/10/13. For personal use only.

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Inflammasomes and Their Roles in Health and Disease Mohamed Lamkanfi1,2 and Vishva M. Dixit3 1

Department of Biochemistry, Ghent University, Ghent 9000, Belgium;

2

Department of Medical Protein Research, VIB, Ghent 9000, Belgium; email: mohamed.lamkanfi@vib-ugent.be 3 Department of Physiological Chemistry, Genentech, South San Francisco, California 94080; email: [email protected]

Annu. Rev. Cell Dev. Biol. 2012. 28:137–61

Keywords

First published online as a Review in Advance on September 10, 2012

NOD-like receptor, caspase, inflammation, infection, cytokine, cell death

The Annual Review of Cell and Developmental Biology is online at cellbio.annualreviews.org This article’s doi: 10.1146/annurev-cellbio-101011-155745 c 2012 by Annual Reviews. Copyright All rights reserved 1081-0706/12/1110-0137$20.00

Abstract Inflammasomes are a set of intracellular protein complexes that enable autocatalytic activation of inflammatory caspases, which drive host and immune responses by releasing cytokines and alarmins into circulation and by inducing pyroptosis, a proinflammatory cell death mode. The inflammasome type mediating these responses varies with the microbial pathogen or stress factor that poses a threat to the organism. Since the discovery that polymorphisms in inflammasome genes are linked to common autoimmune diseases and less frequent periodic fever syndromes, inflammasome signaling has been dissected at the molecular level. In this review, we present recently gained insight on the distinct inflammasome types, their activation and effector mechanisms, and their modulation by microbial virulence factors. In addition, we discuss recently gained knowledge on the role of deregulated inflammasome activity in human autoinflammatory, autoimmune, and infectious diseases.

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INTRODUCTION AND OVERVIEW: PATHOGEN RECOGNITION BY INTRACELLULAR PLATFORM PROTEINS

Contents


INTRODUCTION AND OVERVIEW: PATHOGEN RECOGNITION BY INTRACELLULAR PLATFORM PROTEINS . . . . . . . . . . . . . . . . . . . . . . . Pathogen Recognition: The Foundation of the Innate Immune System . . . . . . . . . . . . . . . . Intracellular and Extracellular Pattern Recognition Receptors . . INFLAMMASOMES: COMPOSITION AND STRUCTURE . . . . . . . . . . . . . . . . . . . . Inflammasomes: Platforms for Inflammatory Caspase Activation . . . . . . . . . . . . . . . . . . . . . . Inflammasome Subtypes . . . . . . . . . . . . INFLAMMASOME EFFECTOR MECHANISMS . . . . . . . . . . . . . . . . . . . Proteolytic Maturation of proIL-1β and proIL-18 . . . . . . . . . . . . . . . . . . . Pyroptosis . . . . . . . . . . . . . . . . . . . . . . . . . Unconventional Secretion of Growth and Inflammatory Factors . . . . . . . . . . . . . . . . . . . . . . . . . Additional Inflammasome Effector Mechanisms . . . . . . . . . . . . . . . . . . . . MECHANISMS OF INFLAMMASOME ACTIVATION . . . . . . . . . . . . . . . . . . . . The Nlrp1 Inflammasome . . . . . . . . . . The Nlrp3 Inflammasome . . . . . . . . . . The Nlrc4 Inflammasome . . . . . . . . . . The Nlrp6 Inflammasome . . . . . . . . . . The AIM2 Inflammasome . . . . . . . . . . INFLAMMASOMES IN AUTOINFLAMMATION AND AUTOIMMUNITY . . . . . . . . . MODULATION OF INFLAMMASOME ACTIVATION AND ACTIVITY . . . . . . . . . . . . . . . . . . . . . . . CONCLUSIONS AND PERSPECTIVES . . . . . . . . . . . . . . . . .

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Pathogen Recognition: The Foundation of the Innate Immune System The human immune system consists of two distinct arms that work in a concerted fashion to respond to harmful stress situations and infectious agents. Activation of immune responses to microbial pathogens and stress factors that pose a threat to the organism start with activation of the evolutionarily more ancient innate immune arm, which temporally precedes and instructs the more recently evolved adaptive immune system. The innate immune system makes use of several mechanisms to counter invasion by harmful agents. These include anatomical barriers such as the skin and mucous membranes that mechanically prevent dispersion throughout the body, opsonization and removal of the invading factor by the complement system, and pattern recognition receptors (PRRs) expressed by hematopoietic and nonhematopoietic cells such as macrophages, dendritic cells, and epithelial cells. PRRs enable innate immune cells to instantly detect and respond to the presence of danger- and pathogen-associated molecular patterns (DAMPs and PAMPs, respectively) (Kanneganti et al. 2007). PAMPs are conserved microbial molecules that are not produced by mammalian host cells, such as nucleic acid structures that are unique to microorganisms, bacterial secretion systems and their effector proteins, and microbial cell wall components such as lipoproteins and lipopolysaccharides (LPSs). Such molecules often are essential for the infectious agent to survive in the host’s hostile environment, which makes them ideal for monitoring of the unwanted presence of microbes by the host’s PRRs. In contrast, DAMPs are a set of host-derived molecules that signal cellular stress, damage, or nonphysiological cell death. High-mobility


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group box 1 (HMGB1), uric acid, ATP, and heat-shock proteins hsp70 and hsp90 are a few examples of DAMPs that are believed to play major roles in eliciting inflammation and tissue repair during infections and under conditions of noninfectious (sterile) inflammation. Engagement of PRRs by PAMPs and DAMPs leads to a multitude of changes in the transcriptional and posttranslational programs of innate immune cells that bring proinflammatory cytokines, chemokines, and growth factors into circulation in a highly coordinated fashion. These molecules signal polymorphonuclear leukocytes and professional phagocytes in the periphery to migrate to the site of infection or injury and at the same time produce additional signals that aim to rapidly eliminate the threat and repair the damage elicited by the pathogen and the host’s inflammatory responses. In addition to these first-line responses, dendritic cells and other professional antigen-presenting cells capture and display immunogenic fragments of the hostile factor on their surface as a way of communicating the identity of the harmful agent to the adaptive immune system (Guermonprez et al. 2002). Through the process of somatic recombination, adaptive immune cells can generate an endless repertoire of antigen-specific receptors and highly specific antibodies against the presented molecules (Call & Wucherpfennig 2005, Di Noia & Neuberger 2007). Such targeted molecules and receptors specifically mark the invading agent expressing the antigen for destruction by the complement and phagocytic activities of the innate immune system or by killer T cells. Thus, the combined qualities of the innate and adaptive immune arms allow highly tailored and efficacious responses to be mounted against a broad range of infections and harmful agents.

Intracellular and Extracellular Pattern Recognition Receptors The human immune system relies on at least four different PRR families to respond to

microbes and harmful particles. Members of the Toll-like receptor (TLR) family line the plasma membrane and endosomal membranes, where they survey the extracellular space for PAMPs and DAMPs (Kawai & Akira 2006, West et al. 2006). More recently, several novel PRR families that appear to guard the intracellular environment have emerged. This includes the RIG-I-like receptor (RLR) as well as the HIN200 and NOD-like receptor (NLR) families (Takeuchi & Akira 2010). Notably, many of these receptors and platform proteins initiate inflammatory signaling pathways that appear partially redundant, which raises the interesting possibility that significant cross talk between members of the same and different PRR families may coordinate host and inflammatory responses (Paludan et al. 2011, Takeuchi & Akira 2010). For instance, TLRs and other PRR families often recognize overlapping sets of PAMPs, including viral RNA (recognized by TLR3 and RLRs) and microbial DNA (recognized by TLR9 and HIN200 proteins). In addition, multiple members of the distinct PRR families engage the inflammatory transcription factors nuclear factor-κB (NF-κB), activator protein 1 (AP1), and interferon regulatory factor (IRF) to induce secretion of cytokines and chemokines with inflammatory and microbicidal properties (Takeuchi & Akira 2010, Tamura et al. 2008). Such redundancy may serve to tailor innate and adaptive immune responses to viral, bacterial, and parasitic pathogens. Unlike most PRRs, however, certain NLR family members and the HIN200 protein absent in melanoma 2 (AIM2) respond to infections and stress by assembling inflammasomes, large cytosolic protein complexes in which inflammatory caspases undergo autocatalytic activation (Kanneganti 2010, Lamkanfi & Dixit 2009). This review provides an overview and discusses our current understanding of the composition of different inflammasomes, their upstream activation and downstream effector mechanisms, and their roles in host defense and disease.

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INFLAMMASOMES: COMPOSITION AND STRUCTURE

Inflammasomes are intracellular multiprotein complexes that mediate activation of the inflammatory caspases-1 and -11 (Kayagaki et al. 2011, Martinon et al. 2002) (Figure 1). This process entails the recruitment of preexisting caspase zymogens into the protein complex, in which they undergo conformational changes associated with their proximity-induced autoactivation (Salvesen & Dixit 1999, Shi 2004). The

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Inflammasomes: Platforms for Inflammatory Caspase Activation

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Figure 1 Domain architecture of inflammasome components. A subset of NLR family members as well as the HIN200 protein AIM2 assemble inflammasome complexes. NLRs are characterized by the combined presence of a NACHT domain followed by a variable number of LRRs. AIM2 contains an amino-terminal PYD followed by a DNA-binding HIN200 domain. Murine Nlrp1b lacks the amino-terminal PYD motif found in human NLRP1. The PYD domains of AIM2 and NLRP1, -3, and -6 recruit the bipartite adaptor protein ASC. NLRP1 and NLRC4 may interact directly with the CARD of caspase-1 or may recruit caspase-1 indirectly through ASC. Human NAIP and its murine paralogs contain BIR motifs in their amino terminus. Abbreviations: AIM2, absent in melanoma 2; ASC, apoptosis-associated speck-like protein containing a CARD; BIR, baculovirus IAP repeat; CARD; caspase recruitment domain; CASP, caspase; FIIND, domain with function to find; LRR, leucine-rich repeat; NACHT, nucleotide-binding and oligomerization domain; NLR, Nod-like receptor; PYD, pyrin. 140

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inflammatory caspases-1 and -11 belong to an evolutionarily conserved family of cysteine proteases that cleave their substrates behind aspartate residues (Lamkanfi et al. 2002). These processing events may cause activation or inactivation of critical signaling cascades regulating programmed cell death, differentiation, and cell proliferation (Lamkanfi et al. 2006). Similar to other caspases that are produced as inactive zymogens with large prodomains, caspases1 and -11 are referred to as initiator caspases (together with caspase-2, -4, -5, -8, -9, -10 and -12). In contrast, caspases containing a short prodomain are known as executioner caspases (caspase-3, -6, -7, and -14) (Figure 2). This segregation of initiator and executioner caspases also is relevant from a functional viewpoint because the large prodomains of initiator caspases typically contain interaction motifs of the death domain superfamily that allow recruitment of the zymogen into activating protein complexes such as the inflammasome and the apoptosome (Lamkanfi & Dixit 2009, Riedl & Salvesen 2007). These homotypic interaction domains typically consist of six or seven antiparallel α-helices, the relative orientation of which determines their classification as caspase recruitment domains (CARDs), pyrin (PYD), death domains, or death effector domains (Park et al. 2007). Initiator caspases most often are further segregated into inflammatory (i.e., caspase-1, -4, -5, -11, and -12) and apoptotic (i.e., caspase-2, -8, -9, and -10) caspases on the basis of their putative roles in inflammatory and apoptosis signaling, respectively. Despite their functional segregation as apoptotic and inflammatory caspases, the activation mechanisms of caspase-1 and -9 are analogous. Both of these CARD-containing initiator caspases are recruited into large cytosolic multiprotein complexes (the apoptosome and the inflammasome, respectively) in which proximity-induced autoactivation is thought to result in mature caspases in which the catalytic domain is autoproteolytically separated from the prodomain. The mature caspase is a heterotetramer of two large and two small catalytic subunits, the interfaces of


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Nlrp1b inflammasome

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Salmonella typhimurium Pseudomonas aeruginosa Legionella pneumophila Shigella flexneri

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Figure 2 Overview of stimuli and models for inflammasome activation. The NLR proteins Nlrp1b, Nlrp3, Nlrc4, and Nlrp6 as well as the HIN200 protein AIM2 assemble inflammasomes in a stimulus-specific manner. Activation of the Nlrp1b inflammasome by cytosolic Bacillus anthracis lethal toxin may involve MKK processing, K+ efflux, phagosomal destabilization, and proteasomal degradation of a currently unknown host factor. Cells exposed to microbial PAMPs, endogenous DAMPs, crystals, particulate matter, or UVB radiation may activate the Nlrp3 inflammasome by eliciting a common cellular response (e.g., ionic fluxes and cytosolic release of lysosomal cathepsins). The Nlrc4 inflammasome is activated indirectly when the PrgJ basal body subunit of the bacterial type III secretion systems of Salmonella, Pseudomonas, Legionella, and Shigella species interacts with Naip2. Nlrc4 also responds to bacterial flagellin, which Naip5 detects in the cytosol of infected cells. AIM2 binds double-stranded DNA in the cytosol of cells infected with Francisella tularensis, Listeria monocytogenes, and the DNA viruses cytomegalovirus and vaccinia virus. The microbial ligands responsible for activation of the Nlrp6 inflammasome in the gastrointestinal tract remain to be identified. Abbreviations: AIM2, absent in melanoma 2; BIR, baculovirus IAP repeat; CARD; caspase recruitment domain; DAMP, danger-associated molecular pattern; FIIND, domain with function to find; LRR, leucine-rich repeat; MKK, mitogen-activated protein kinase kinase; NACHT, nucleotide-binding and oligomerization domain; NLR, Nod-like receptor; PAMP, pathogen-associated molecular pattern; PYD, pyrin.

which form the two active sites at opposing ends of the molecule (Salvesen & Riedl 2008). Moreover, both complexes consume ATP, and electron micrographs of inflammasome and apoptosome particles revealed that both of these complexes have a double-ringed wheel structure with sevenfold symmetry (Acehan et al. 2002, Faustin et al. 2007).

Inflammasome Subtypes Inflammasomes are emerging as key regulators of innate, adaptive, and host responses

that survey the cytosol and other intracellular compartments for the presence of PAMPs and DAMPs (Kanneganti 2010, Lamkanfi & Dixit 2009). These multiprotein complexes have been characterized in a variety of cells, although the focus has been mainly on epithelial cells in tissues with mucosal surfaces and immune cells of the myeloid lineage. Several inflammasome complexes have been distinguished, each typically named after the NLR or HIN200 protein that initiates signaling (Kanneganti 2010, Lamkanfi & Dixit 2009) (Figure 2). Recent www.annualreviews.org • Inflammasome Signaling in Disease

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gene duplication events that occurred after the bifurcation of rodents and primates gave rise to 34 NLR genes in the mouse genome (Tian et al. 2009). The corresponding gene family in humans consists of 22 members, each containing a centrally located nucleotide-binding and oligomerization domain (NACHT) motif (Figure 1). This ATPase domain is usually flanked at the amino terminus by CARD, PYD, or baculovirus IAP repeat (BIR) motifs, which allow NLRs to recruit adaptor proteins and downstream effectors to their signaling complexes. The leucine-rich repeats (LRRs) found at the carboxy terminus of most NLRs are generally thought—in analogy to their role in TLRs—to be responsible for detecting and monitoring the presence of PAMPs and DAMPs in intracellular compartments. In addition, LRRs are believed to modulate NLR activity (Kanneganti et al. 2007). Biochemical and in vivo analysis of gene-deficient mice revealed central roles for the NLR proteins Nlp1b, Nlrp3, Nlrp6, and Nlrc4 in inflammasome signaling (Kanneganti 2010, Lamkanfi & Dixit 2009). Nlrp3 and Nlrp6 lack a CARD motif and cannot interact directly with caspase-1. In their respective inflammasomes, the amino-terminal PYD of the bipartite adaptor apoptosis-associated speck-like protein containing a CARD (ASC) interacts with the upstream NLR, whereas its carboxy-terminal CARD facilitates the recruitment of caspase-1. Consequently, ASC is essential for assembly and activation of these PYD-containing inflammasomes (Agostini et al. 2004, Elinav et al. 2011, Kanneganti et al. 2006, Mariathasan et al. 2006, Sutterwala et al. 2006). ASC probably also plays a key role in the CARD-containing Nlrp1b and Nlrc4 inflammasomes (Mariathasan et al. 2004, 2006; Sutterwala et al. 2007), although these NLRs may also interact directly with caspase-1. In this regard, Nlrc4 was recently suggested to assemble two distinct inflammasome complexes, one that contains and one that lacks ASC (Broz et al. 2010). The ASC-containing Nlrc4 inflammasome induces caspase-1 autoproteolysis and cytokine maturation, whereas the complex lacking


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ASC triggers caspase-1-dependent cell death in the absence of caspase-1 autoprocessing. In addition to the above NLR-containing inflammasomes, AIM2 also assembles an inflammasome. AIM2 contains a prototypical DNA-binding HIN200 domain that is preceded by an amino-terminal PYD motif through which it recruits ASC and caspase-1 into the complex (Figure 1).

INFLAMMASOME EFFECTOR MECHANISMS Proteolytic Maturation of proIL-1β and proIL-18 The best-characterized consequence of caspase-1 activation in the inflammasomes described above is secretion of the proinflammatory cytokines interleukin (IL)-1β and IL-18 (Figure 3). These related cytokines are produced as inactive propeptides that need to be processed in order to be secreted from activated monocytes, macrophages, and other cell types (Dinarello 2009, Sims & Smith 2010). Caspase-1 was originally identified as the IL-1β-converting enzyme and subsequently demonstrated to be required for maturation of IL-18 as well (Cerretti et al. 1992, Ghayur et al. 1997, Gu et al. 1997, Kuida et al. 1995, Li et al. 1995). Consequently, caspase-1-deficient mice and macrophages fail to secrete mature IL-1β and IL-18 under most circumstances (Ghayur et al. 1997, Gu et al. 1997, Kuida et al. 1995, Li et al. 1995), although proteases such as neutrophil serine proteinase-3 and granzyme A also mediate secretion of mature IL-1β in specific mouse models of human disease (Guma et al. 2009, Joosten et al. 2009, Mayer-Barber et al. 2010). This raises the interesting possibility that redundant mechanisms for secretion of mature IL-1β may have evolved for safeguarding the host’s immune response against pathogens that interfere with inflammasome activation and caspase-1 activity (see below). Once secreted, IL-1β and IL-18 mediate a variety of local and systemic responses to infection. IL-1β induces fever; promotes T cell survival, B cell proliferation, and


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antibody production; contributes to polarization of T helper 1 (TH 1), TH 2, and TH 17 responses; and mediates transmigration of leukocytes (Dinarello 2009, Sims & Smith 2010). Although IL-18 does not induce fever responses, it synergizes with IL-12 to induce interferon-γ (IFNγ) production by activated T cells and natural killer cells, thereby promoting TH 1 cell polarization (Dinarello 2009, Sims & Smith 2010). IL-18 also drives TH 17 responses by facilitating the production of IL-17 from already committed TH 17 cells cultured in the presence of IL-23 (Harrington et al. 2005, Weaver et al. 2006). In the absence of IL-12 and IL-23, IL-18 may promote TH 2 responses by stimulating the production of IL-4, IL-5, and other TH 2 cytokines (Dinarello 2009, Hoshino et al. 2001, Nakanishi et al. 2001). In conclusion, IL-1β and IL-18 are important inflammasome effectors. This is also illustrated by the successful application of IL-1 inhibitors in patients suffering from hereditary autoinflammatory disorders, gouty arthritis, and type II diabetes (Lachmann et al. 2009, Lamkanfi et al. 2011, Larsen et al. 2007).

Pyroptosis Despite the importance of IL-1β and IL-18 in inflammasome signaling, several lines of evidence point to a range of additional inflammasome effector mechanisms that may contribute to immune and host responses. For example, mice lacking IL-1β and IL-18 were shown to be less susceptible to Francisella tularensis infection than those lacking caspase-1 (Henry & Monack 2007). The notion that neutralization of IL-1β and IL-18 does not abrogate all inflammasome functions is further illustrated by the observation that mice lacking both IL-1β and IL-18 are susceptible to LPSinduced shock, whereas caspase-1 knockout mice are resistant (Lamkanfi et al. 2010). Moreover, caspase-1-mediated host responses to Legionella pneumophila, Burkholderia thailandensis, and a mutant flagellin-expressing Salmonella

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Figure 3 Canonical and noncanonical activation of the Nlrp3 inflammasome. Cells stimulated with ATP, silica, and uric acid crystals induce maturation and secretion of IL-1β and IL-18, unconventional secretion of DAMPs, and pyroptotic cell death by activating caspase-1 through the canonical Nlrp3 inflammasome. In contrast, noncanonical activation of caspase-1 by Escherichia coli, Citrobacter rodentium, and Vibrio cholerae requires caspase-11 in addition to the regular Nlrp3 inflammasome. Noncanonical activation of caspase-1 induces maturation and secretion of IL-1β and IL-18, whereas pyroptosis and DAMP secretion proceed directly through caspase-11. Abbreviations: CASP, caspase; DAMP, danger-associated molecular pattern; HMGB1, high-mobility group box 1; IL, interleukin; NLR, Nod-like receptor; PAMP, pathogen-associated molecular pattern.

typhimurium strain only partially relied on IL-1β and IL-18 (Miao et al. 2010a). The last study characterized pyroptosis, a proinflammatory cell death mode that requires caspase-1 activity, as a critical mechanism by which inflammasomes contribute to host responses against gram-negative bacterial pathogens in vivo. Pyroptosis was also implicated in clearance of the gram-positive pathogen Bacillus www.annualreviews.org • Inflammasome Signaling in Disease

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anthracis in vivo (Terra et al. 2010). Pyroptotic cell death has mainly been characterized in myeloid cells infected with pathogenic bacteria such as Shigella flexneri, S. typhimurium, Pseudomonas aeruginosa, L. pneumophila, B. anthracis, Staphylococcus aureus, Listeria monocytogenes, and F. tularensis (Chen et al. 1996, Hilbi et al. 1998, Jones et al. 2010, Lamkanfi & Dixit 2010, Miao et al. 2010a, Terra et al. 2010), but it may affect cells of the central nervous system and the cardiovascular systems under ischemic conditions as well (Bergsbaken et al. 2009). This genetically programmed cell death mode differs morphologically from apoptosis in that it features cytoplasmic swelling and early plasma membrane rupture (Lamkanfi & Dixit 2010). The consequent release of the cytoplasmic content into the extracellular space is thought to render pyroptosis proinflammatory, whereas apoptosis is generally considered an immunologically silent cell death mechanism (Lamkanfi 2011, Taylor et al. 2008). However, apoptosis and pyroptosis also share several biochemical features such as the requirement for caspase activity (albeit the caspases involved differ), condensation of the nuclear compartment, and oligonucleosomal fragmentation of genomic DNA (Lamkanfi & Dixit 2010). Although the biochemical pathway by which caspase-1 activation induces pyroptosis largely remains to be elucidated, this cell death mode proceeds independently of IL-1β and IL-18 (Lamkanfi et al. 2008; Miao et al. 2010a; Monack et al. 1996, 2001). In vivo, pyroptosis may represent a mechanism that prevents intracellular replication of infectious agents by eliminating the infected macrophages and dendritic cells altogether. By releasing their intracellular content into circulation, pyroptotic cells may simultaneously target surviving bacteria for destruction by phagocytes and neutrophils and alert other immune cells to imminent danger (Miao et al. 2010a). Altogether, pyroptosis is emerging as an intriguing inflammasome-mediated host defense mechanism against intracellular pathogens.


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Unconventional Secretion of Growth and Inflammatory Factors A third emerging mechanism by which inflammasomes may contribute to immune signaling is the secretion of leaderless cytokines and growth factors (Figure 3). Unlike conventionally secreted factors, these proteins lack signal peptides to direct them to the translocation apparatus of the classical endoplasmic reticulum (ER)-Golgi complex pathway (Lee et al. 2004, Trombetta & Parodi 2003). In fact, IL-1β and IL-18 were two of the first proteins recognized to be exported independently of the ER–Golgi complex (Rubartelli et al. 1990). Recent studies have extended the list of unconventionally secreted cytokines and growth factors to more than 20 proteins, including the DAMP HMGB1, the IL-1β-related cytokine IL-1α, growth factors such as fibroblast growth factor 2 (FGF2), and the lectins galectin-1 and -3 (Nickel & Rabouille 2009). The biochemical mechanism(s) by which leaderless proteins are secreted into the extracellular space largely remains to be characterized, but inflammasomes might play a central role in this process. In addition to the expected defects in the secretion of mature IL-1β and IL-18, monocytes and macrophages lacking the inflammasome components Nlrp3, ASC, and caspase-1 also failed to secrete normal levels of IL-1α after LPS stimulation (Kuida et al. 1995, Sutterwala et al. 2006). Similarly, caspase-1 was required for secretion of FGF2 by macrophages, UVA-irradiated fibroblasts, and UVB-irradiated keratinocytes (Keller et al. 2008). Finally, components of the Nlrp3 and Nlrc4 inflammasomes also were required for extracellular release of HMGB1 from LPS-activated and infected macrophages (Lamkanfi et al. 2010). Unlike IL-1β and IL-18, caspase-1 does not process secreted IL-1α, FGF2, and HMGB1 (Dinarello 2009, Keller et al. 2008, Lamkanfi et al. 2010), which suggests that inflammasomes may indirectly regulate unconventional protein secretion. In this respect, the secretion of leaderless proteins was proposed to occur in shed microvesicles,


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secretory lysosomes, or exosomes (Nickel & Rabouille 2009), but whether caspase-1 regulates the trafficking of such membrane-bound particles remains to be determined. What has become clear, however, is that the release of different leaderless client proteins is not necessarily interdependent. For instance, although S. typhimurium-infected macrophages simultaneously secrete IL-1β, IL-18, and HMGB1, secretion of the last proceeds unhampered in macrophages lacking both IL-1β and IL-18 (Lamkanfi et al. 2010). More importantly, caspase-1 enzymatic activity appears to be required for the secretion of leaderless proteins. Indeed, pharmacological inhibition of caspase1 not only prevented secretion of IL-1β and IL-18 but also affected the release of IL-1α from LPS-activated peritoneal macrophages and UVB-irradiated keratinocytes (Keller et al. 2008). Similarly, HMGB1 release from LPS-primed and S. typhimurium-infected macrophages was impaired by the caspase-1 inhibitor Ac-YVAD-cmk (Lamkanfi et al. 2010). These observations suggest that caspase-1 may activate a secretion apparatus of unknown identity by cleaving a regulatory factor. The small GTPase Rab39a was recently suggested as a caspase-1 substrate that may be involved in secretion of IL-1β from LPS-activated THP-1 cells (Becker et al. 2009). However, further study is required to determine whether Rab39a plays a role in secretion of other leaderless proteins and to examine how caspase-1-mediated processing affects its functions. Alternatively, caspase-1-mediated release of leaderless proteins might be coupled to pyroptosis. Further characterization of these processes undoubtedly will shed more light on this matter.

Additional Inflammasome Effector Mechanisms Apart from the effector mechanisms described above, inflammasomes have been implicated in inactivation of glycolysis enzymes (Shao et al. 2007), activation of sterol-regulatory element binding protein-1 and -2 (Gonzalez et al. 2008), and activation of the executioner caspase-7

during L. pneumophila and S. typhimurium infection (Akhter et al. 2009, Lamkanfi et al. 2008). Together, these mechanisms illustrate that inflammasomes can contribute to a diverse set of responses that collectively may help the host to effectively fight microbial pathogens and other threats (Lamkanfi 2011).

MECHANISMS OF INFLAMMASOME ACTIVATION The Nlrp1 Inflammasome An intriguing aspect of inflammasome biology is that their assembly and activation proceed in a signal-specific manner (Figure 2). For example, the cytosolic presence of B. anthracis lethal toxin specifically alerts NLRP1 (Boyden & Dietrich 2006). This toxin is the major cause of death in systemic anthrax (Dixon et al. 1999, Friedlander 2001). The protective antigen subunit of the toxin allows the metalloprotease effector subunit lethal factor (LF) to enter the cytosol of infected host cells. Humans express NLRP1 from a single gene, whereas the murine genome encodes three tandem paralogs (Nlrp1a, Nlrp1b, and Nlrp1c) (Boyden & Dietrich 2006). Strong genetic evidence points to Nlrp1b as a key susceptibility locus for LT-induced caspase-1 activation and pyroptosis induction (Boyden & Dietrich 2006). First, macrophages from 129S1 mice are susceptible to LF intoxication and express Nlrp1b but not Nlrp1a or Nlrp1c (Boyden & Dietrich 2006). Second, Nlrp1b is highly polymorphic; five different gene variants have been identified in a set of 18 inbred mouse strains. Notably, susceptibility to LF-induced pyroptosis perfectly matched these variations in Nlrp1b (Boyden & Dietrich 2006). Third, wild-type C57BL/6 macrophages carry a dysfunctional Nlrp1b allele, but C57BL/6 mice transgenically expressing a functional Nlrp1b variant from 129S1 mice are susceptible to LF-induced caspase-1 activation and pyroptosis induction (Boyden & Dietrich 2006). In analogy to TLRs, Nlrp1b was initially assumed to bind cytosolic LF directly through www.annualreviews.org • Inflammasome Signaling in Disease

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its LRR motifs. However, that LF metalloprotease activity is required for activation of the Nlrp1b inflammasome suggested that Nlrp1b indirectly senses the cytosolic presence of LF through the cleavage of host substrates rather than through direct binding of the microbial protease (Fink et al. 2008). LF-mediated cleavage of mitogen-activated protein (MAP) kinase kinases (MKKs) leads to impaired activation of the downstream MAP kinases p38, ERK, and JNK (Duesbery et al. 1998). Inhibition of p38 and Akt was recently suggested to trigger ATP release through connexin-43 channels, which in turn causes K+ efflux and Nlrp1b activation downstream of the purinergic P2X7 receptor (Ali et al. 2011). Ca2+ fluxes and proteasome activation were also proposed to act upstream of Nlrp1b activation (Fink et al. 2008, Muehlbauer et al. 2010, Wickliffe et al. 2008). Finally, LF-induced activation of Nlrp1b was suggested to involve cleavage of a currently unknown host factor by cathepsin B released from destabilized lysosomes (Newman et al. 2009). Regardless of the precise mechanism inducing Nlrp1b activation, lethal toxin–mediated activation of the Nlrp1b inflammasome clearly represents a key host defense mechanism for controlling infection with B. anthracis spores in vivo (Terra et al. 2010). Both pyroptosis and signaling downstream of the IL-1 receptor have been proposed to contribute to inflammasomemediated resistance against B. anthracis infection (Ali et al. 2011, Terra et al. 2010). Future studies should focus on further characterizing the mechanisms leading to Nlrp1b activation and on determining whether Nlrp1a and Nrlp1c also assemble inflammasomes.


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The Nlrp3 Inflammasome The importance of inflammasome signaling to host defense responses is not limited to B. anthracis infection. The Nlrp3 inflammasome especially has been implicated in responses to a broad spectrum of infectious agents, including the bacterial pathogens S. aureus, Vibrio cholerae, Escherichia coli, Neisseria gonorrhoeae, Chlamydia pneumoniae, and Citrobacter rodentium (Duncan 146

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et al. 2009, He et al. 2010, Kayagaki et al. 2011, Shimada et al. 2011, Toma et al. 2010); the fungal pathogens Candida albicans and Aspergillus fumigatus (Gross et al. 2009, Hise et al. 2009, Joly et al. 2009, Said-Sadier et al. 2010); viral pathogens such as influenza A, encephalomyocarditis virus, and vesicular stomatitis virus (Allen et al. 2009, Ichinohe et al. 2010, Rajan et al. 2011, Thomas et al. 2009); and the parasites Schistosoma mansoni and Dermatophagoides pteronyssinus (Dai et al. 2011, Ritter et al. 2010). The large set of pathogens activating Nlrp3 suggests that this NLR senses microbes indirectly by monitoring the levels of a host-derived DAMP that is produced or released as a consequence of cellular or tissue injury elicited by toxins of the infectious agent (Lamkanfi & Dixit 2009) (Figure 2). Indeed, DAMPs such as ATP, uric acid crystals, amyloid-β fibrils, and hyaluronan all activate Nlrp3 (Halle et al. 2008, Mariathasan et al. 2006, Martinon et al. 2006, Yamasaki et al. 2009). Crystalline particles such as amyloid fibrils, alum, silica, asbestos, and nanomaterials may simulate the effects of microbial toxins and lead to Nlrp3 activation through similar mechanisms (Tschopp & Schroder 2010). Given the wide array of molecules inducing activation of the Nlrp3 inflammasome, its activation is tightly regulated at multiple levels. Unlike other inflammasomeactivating NLRs, Nlrp3 is expressed at very low levels in naive macrophages and dendritic cells. Consequently, NF-κB-driven upregulation of Nlrp3 transcripts is a first necessity for activation of this inflammasome (Bauernfeind et al. 2009). However, priming alone is not sufficient, because Nlrp3 inflammasome activation occurs only in TLR-activated cells that are subsequently exposed to bacterial toxins, DAMPs, or crystalline substances (Lamkanfi & Dixit 2009, Tschopp & Schroder 2010). Although how Nlrp3 is activated remains unclear, three putative mechanisms have been formulated. The first involves K+ efflux through the purinergic P2X7 receptor and other ion channels and pore-forming toxins such as nigericin, maitotoxin, and hemolysins (Franchi et al. 2007a, Perregaux & Gabel 1994,


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Petrilli et al. 2007, Walev et al. 1995). However, the above ion channels and cytotoxins also modulate the cellular concentrations of H+ , Na+ , and Ca2+ , which suggests that ion fluxes in general may impact Nlrp3 activation (Lamkanfi & Dixit 2009). In this regard, Nlrp3 activation by phagocytosed uric acid crystals was recently proposed to involve a massive influx of Na+ ; the ensuing influx of water and drop in intracellular K+ concentrations compensate for the rise in intracellular osmolarity (Schorn et al. 2011). Moreover, the influenza M2 channel deacidifies the Golgi complex lumen by exporting H+ ions into the cytosol, which in turn trigger Nlrp3 activation (Ichinohe et al. 2010). However, K+ and other ion fluxes also have been implicated in activation of the Nlrp1b (Ali et al. 2011, Fink et al. 2008, Newman et al. 2009, Wickliffe et al. 2008) and Nlrc4 inflammasomes (Arlehamn et al. 2010). Thus, although ion fluxes may modulate the threshold for caspase-1 activation, they are unlikely to represent a specific signal directly leading to assembly of specific inflammasomes (Lamkanfi & Dixit 2009). A second proposal suggests that mitochondrial reactive oxygen species (ROS) account for Nlrp3 activation. This notion is based on the observation that all Nlrp3-activating molecules, such as ATP, nigericin, alum, and uric acid, induce ROS production in macrophages and monocytes (Cruz et al. 2007, Zhou et al. 2011). However, TLR signaling is also accompanied by ROS production but nevertheless fails to activate the Nlrp3 inflammasome in the absence of a second challenge. Concurrently, recent studies implicated mitochondrial ROS in the NF-κB-mediated upregulation of Nlrp3 and proIL-1β transcripts rather than in Nlrp3 inflammasome activation per se (Bauernfeind et al. 2011, Bulua et al. 2011). The third model proposes that phagosomal destabilization and cytosolic release of lysosomal cathepsins drive Nlrp3 activation. Indeed, phagocytosis of crystalline and particulate molecules may cause damage to the lysosomal membrane, which consequently leads to leakage of lysosomal cathepsins into the cytosol. In this regard, cathepsin B–mediated processing

of a cytosolic factor was suggested to act upstream of Nlrp3 activation by silica, alum, and amyloid-β fibrils (Halle et al. 2008, Hornung et al. 2008). Cytosolic release of cathepsin B was also implicated in caspase-1 activation by the ionophore nigericin (Hentze et al. 2003), which suggests a unifying mechanism for Nlrp3 activation by both particulate and nonparticulate stimuli. However, the observation that activation of the Nlrp3 inflammasome was not affected in cathepsin B-deficient macrophages exposed to malarial hemozoin, uric acid crystals, silica, and alum suggests redundancy with other cathepsins or other pathways leading to Nlrp3 activation (Dostert et al. 2009, Tschopp & Schroder 2010). In this regard, a recent study showed that live bacteria activate the Nlrp3 inflammasome in a TIR-domain-containing adaptor-inducing interferon-β (TRIF)-dependent manner owing to the leakage of microbial mRNAs from damaged phagosomes into the cytosol (Sander et al. 2011). The absence of a 3 polyadenylyl tail that is characteristic of eukaryotic mRNAs appears critical for Nlrp3 inflammasome activation by microbial RNAs. Because mRNAs are intrinsically unstable, Nlrp3 inflammasome–mediated recognition of microbial RNAs may represent an innate immune mechanism that distinguishes live from dead microbes (Sander et al. 2011). Although further clarification of the molecular mechanisms leading to Nlrp3 activation is required, an intriguing role was recently revealed for mouse caspase-11 (Kayagaki et al. 2011). This caspase-1-related protease is represented by caspases-4 and -5 in the human genome (Lamkanfi et al. 2002). Although caspase-11 was dispensable for caspase-1 activation by canonical Nlrp3 activators such as ATP and nigericin, it proved essential for caspase-1 maturation and IL-1β secretion from macrophages infected with the enteric bacteria E. coli, C. rodentium, and V. cholerae (Kayagaki et al. 2011) (Figure 3). Caspase-11 also mediates noncanonical activation of the Nlrp3 inflammasome in vivo during LPSinduced endotoxemia (Kayagaki et al. 2011, Wang et al. 1998). In keeping with this notion, www.annualreviews.org • Inflammasome Signaling in Disease

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caspase-11-deficient mice had less IL-β and IL18 in circulation (Kayagaki et al. 2011, Wang et al. 1998). Moreover, they were markedly resistant to lethal doses of LPS (Kayagaki et al. 2011, Wang et al. 1998). Caspase-1 was initially also implicated in protection against LPS-induced lethality on the basis of the resistant phenotype of published caspase-1 knockout mice (Kuida et al. 1995, Li et al. 1995). However, it recently emerged that these mice also lack caspase-11 expression owing to a mutation in the caspase-11 locus of 129S mice, embryonic stem cells of which were used to generate available caspase-1−/− mice (Kayagaki et al. 2011). Caspase-11 expression in these apparent double knockout mice was restored from an appropriate C57BL/6 bacterial artificial chromosome, and subsequent studies with these transgenic mice revealed that caspase-1 deficiency alone provided only mild protection against LPS-induced lethality (Kayagaki et al. 2011). Concurrently, mice lacking both IL-1β and IL-18 were demonstrated to be susceptible to LPS-induced lethality (Lamkanfi et al. 2010). In agreement with these findings, mice lacking Nlrp3 or ASC failed to produce IL-1β and IL-18 when challenged with high doses of LPS but survived only slightly longer than wildtype mice (Kayagaki et al. 2011). Nevertheless, Nlrp3-dependent IL-1β and IL-18 production may provide an amplification signal given that Nlrp3−/− and Asc−/− mice were relatively resistant to shock when challenged with lower doses of LPS (Mariathasan et al. 2004, 2006). Importantly, these observations suggest that caspase-11 may induce tissue damage and lethality independently of caspase-1. Indeed, LPS-induced serum levels of the DAMP IL-1α were significantly reduced in mice lacking both caspases-1 and -11 and in those deficient only for caspase-11 (Kayagaki et al. 2011). In contrast, transgenic mice lacking only caspase-1 had high levels of IL-1α in circulation. Moreover, pyroptotic cell death and release of IL-1α and HMGB1 from macrophages infected with E. coli, C. rodentium, and V. cholerae required caspase-11, but not Nlrp3, ASC, or caspase-1 (Kayagaki et al.


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2011). Clearly, these observations warrant further inspection of the mechanisms leading to caspase-11 activation and the pathways by which it exerts its downstream functions.

The Nlrc4 Inflammasome Unlike the Nlrp3 inflammasome, Nlrc4 is currently thought to respond to only two bacterial components: flagellin and the PrgJ basal body of bacterial type III secretion systems (Miao et al. 2010b) (Figure 2). Consequently, facultative intracellular pathogens expressing these factors, such as S. typhimurium, S. flexneri, P. aeruginosa, B. thailandensis, and L. pneumophila, all activate the Nlrc4 inflammasome (Amer et al. 2006; Franchi et al. 2006, 2007b; Lamkanfi et al. 2007; Mariathasan et al. 2004; Miao et al. 2006, 2008, 2010a; Sutterwala et al. 2007; Suzuki et al. 2007). The BIR-containing NLRs Naip2 and Naip5 link Nlrc4 to recognition of PrgJ and flagellin, respectively (Kofoed & Vance 2011, Zhao et al. 2011). The murine Naip subfamily consists of seven NLR family members (Naip1–7), four of which (Naip-1, -2, -5, and -6) are expressed in C57BL/6 mice (Wright et al. 2003). The observation that Naip2 and Naip5 recruit PrgJ and flagellin begs the question of whether detection of bacterial factors by Naip proteins represents a general mechanism conferring specificity to distinct inflammasomes. This appears unlikely, however, given that humans encode a single NAIP protein. Mutations in human NAIP are linked to spinal muscular atrophy (Roy et al. 1995), but whether these mutations also increase susceptibility to bacterial infections is not known. Notably, unlike mouse macrophages, human monocytes and macrophages appear resistant to inflammasome activation by bacterial flagellin and PrgJ-like rod proteins (Zhao et al. 2011). Instead, human NAIP activates the NLRC4 inflammasome upon detection of Chromobacterium violaceum CprI and homologous needle subunits of the type III secretion apparatus of S. typhimurium, B. thailandensis, P. aeruginosa, and S. flexneri (Zhao et al. 2011).


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These observations raise doubt regarding the importance of inflammasome-mediated flagellin recognition in human infections. They also suggest that Naip proteins may contribute to immunity in several ways. In this regard, naturally occurring mutations in Naip5 render A/J mice and macrophages highly susceptible to L. pneumophila infection but fail to prevent flagellin-induced activation of the Nlrc4 inflammasome (Lamkanfi et al. 2007, Lightfield et al. 2008, Miao et al. 2008). These mutations markedly reduce Naip5 expression levels in A/J macrophages relative to C57BL/6 macrophages (Wright et al. 2003). Although the precise mechanism by which Naip5 regulates L. pneumophila clearance in A/J macrophages remains unclear, it may regulate cell death and maturation of Legionella-containing phagosomes (Akhter et al. 2009, Fortier et al. 2007). Thus, further characterization of murine Naip proteins is required to fully understand their roles in innate immune signaling.

The Nlrp6 Inflammasome The roles of Nlrp6 in inflammasome signaling are less established. Nlrp6-deficient mice are more susceptible to dextran sodium sulfate (DSS)-induced colitis and inflammationassociated colon tumorigenesis (Chen et al. 2011, Elinav et al. 2011, Normand et al. 2011). Interestingly, in one study Nlrp6 deficiency caused marked changes in the composition of intestinal flora characterized by an increased presence of pathogenic Prevotellaceae and TM7 species (Elinav et al. 2011). Similar changes in the microflora were observed in mice lacking ASC, caspase-1, and IL-18, which suggests that assembly of a functional Nlrp6 inflammasome is required for maintenance of a healthy colonic microflora (Elinav et al. 2011). Strikingly, the exacerbated colitis phenotype of Asc−/− animals could be transferred to cohoused and cross-fostered wild-type mice, which suggests that the skewed microflora in Asc−/− and Nlrp6−/− mice was the main colitogenic factor driving increased colitis severity in these mice (Elinav et al. 2011). A

detailed biochemical characterization of this signaling pathway awaits the identification of specific PAMPs and DAMPs that can induce assembly of the Nlrp6 inflammasome in isolated epithelial and hematopoietic cells.

The AIM2 Inflammasome In addition to the NLRs above, the HIN200 family member AIM2 was recently shown to assemble an inflammasome that is critical for activating caspase-1 in macrophages infected with F. tularensis and in response to DNA viruses such as cytomegalovirus and vaccinia virus (Fernandes-Alnemri et al. 2010, Jones et al. 2010, Rathinam et al. 2010, Sauer et al. 2010). In association with Nlrp3 and Nlrc4, the AIM2 inflammasome also contributes to caspase-1 activation by L. monocytogenes (Rathinam et al. 2010, Sauer et al. 2010). Similar to AIM2, the three remaining human HIN200 proteins (named IFI16, MNDA, and IFIX) combine an amino-terminal PYD domain with one or two carboxy-terminal doublestranded (ds)DNA-binding HIN200 motifs. However, the latter three HIN200 proteins are present in the nuclear compartment of resting macrophages and dendritic cells, whereas AIM2 is found in the cytosol (Burckstummer et al. 2009). This suggests that AIM2 may recognize replicating microbes in the cytosol of infected macrophages by means of a direct association between its HIN200 domain and genomic material of the infectious agent. Ensuing conformational changes may induce an open conformation that allows recruitment of ASC and caspase-1 through AIM2’s amino-terminal PYD. Although AIM2 may not encounter selfDNA under normal conditions, transfection of synthetic and mammalian dsDNA nevertheless induced activation of the AIM2 inflammasome (Burckstummer et al. 2009, Fernandes-Alnemri et al. 2009, Hornung et al. 2009). Together with the observation that AIM2 deficiency stimulates the expression of the interferon-inducible lupus susceptibility gene Ifi202 (Panchanathan et al. 2010), this suggests that inactivating mutations in AIM2 may increase susceptibility www.annualreviews.org • Inflammasome Signaling in Disease

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to autoimmune diseases in which reactions against self-DNA play an important role.

INFLAMMASOMES IN AUTOINFLAMMATION AND AUTOIMMUNITY


Recent years have seen significant progress in our understanding of how inflammasomes contribute to the molecular pathology of multiple autoinflammatory and autoimmune diseases. Two studies linked single-nucleotide polymorphisms (SNPs) in the promoter and coding regions of NLRP1 with increased incidence of vitiligo and vitiligo-associated Addison’s disease, respectively ( Jin et al. 2007a,b). Vitiligo is a rare autoimmune disease that is characterized by depigmentation of the skin and hair, whereas the adrenal cortex of patients with Addison’s disease is attacked by the immune system and gradually becomes impaired in the production of glucocorticoids and adrenal androgen. Notably, a SNP in the NLRP1 open reading frame (SNP rs12150220) also strongly linked to Addison’s disease in the absence of vitiligo (Magitta et al. 2009, Zurawek et al. 2010). Because most identified SNPs in NLRP1 (including rs12150220) are located in and around the central NACHT domain, they are thought to reduce the threshold for inflammasome assembly and IL-1β production ( Jin et al. 2007b). If this model holds, caspase-1 inhibitors and IL-1β neutralizing therapies may be used for treating vitiligo and Addison’s disease patients carrying NLRP1 SNPs. As with NLRP1, gain-of-function mutations in and around the NLRP3 NACHT domain have been associated with a spectrum of hereditary autoinflammatory diseases that are collectively referred to as cryopyrinassociated periodic syndromes (CAPS). The primary symptoms of CAPS patients are urticarial skin rashes and prolonged episodes of fever, but arthralgia, sensorineural hearing loss, headaches, elevated spinal fluid pressure, cognitive deficits, and renal amyloidosis also may be observed (Feldmann et al. 2002, Hoffman et al. 2001). Apart from the bony overgrowth 150

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seen in some CAPS patients, excessive production of IL-1β and IL-18 by mononuclear cells may explain most of these symptoms. Indeed, the contribution of excessive IL-1β levels was recently confirmed in mice expressing CAPSassociated Nlrp3 variants (Brydges et al. 2009, Meng et al. 2009). Moreover, IL-1 neutralizing therapies proved highly beneficial in CAPS patients (Hawkins et al. 2003; Hoffman et al. 2004, 2008; Lachmann et al. 2009). Notably, another set of SNPs in the NLRP3 promoter have been associated with increased susceptibility to Crohn’s disease in humans. These polymorphisms caused decreased NLRP3 expression and reduced IL-1β production in cells stimulated with TLR agonists (Villani et al. 2009). In addition, polymorphisms in IL-18 correlated with increased susceptibility to Crohn’s disease (Tamura et al. 2002). Further insight into the roles of Nlrp3 and IL-18 in protection against intestinal inflammation came from the analysis of genedeficient mice. Nlrp3−/− mice presented with increased body weight loss, rectal bleeding, diarrhea, and mortality when subjected to DSSand 2,4,6-trinitrobenzene sulfonate–induced colitis, which confirms that Nlrp3 expression is required for protection against gastrointestinal inflammation (Allen et al. 2010, Hirota et al. 2010, Zaki et al. 2010a). The critical role of inflammasome signaling in protection against colon inflammation was confirmed in mice lacking ASC and caspase-1 (Allen et al. 2010, Dupaul-Chicoine et al. 2010, Zaki et al. 2010a) as well as in animals lacking IL-1β and IL-18 or their cognate receptors (Lebeis et al. 2009, Salcedo et al. 2010, Takagi et al. 2003). Mice lacking components of the Nlrp3 inflammasome also suffered from increased dysplasia and tumor formation in the azoxymethane/DSS tumorigenesis model (Allen et al. 2010, Zaki et al. 2010b). Furthermore, mice lacking Nlrc4 were protected from tumor formation (Hu et al. 2010), which points to a key role for inflammasome signaling in regulating gut homeostasis and colon tumorigenesis. Finally, inflammasome signaling might contribute to multiple sclerosis, as it was shown


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to exacerbate disease progression in the experimental autoimmune encephalomyelitis (EAE) mouse model. Indeed, mice lacking Nlrp3 and ASC were protected from EAE development because of reduced TH 1 and TH 17 responses (Gris et al. 2010, Shaw et al. 2010). This protective phenotype was attributed to defective caspase-1 activation and IL-18 secretion because caspase-1−/− and il-18−/− mice were also protected (Furlan et al. 1999, Gris et al. 2010, Shaw et al. 2010). Further insight into how inflammasomes regulate neuronal inflammation may pave the way for the development of novel therapeutic options for this debilitating disease.

MODULATION OF INFLAMMASOME ACTIVATION AND ACTIVITY Inflammasome activation contributes significantly to host and inflammatory responses, but the association of gain-of-function mutations in NLRP3, NLRP1, and other inflammasome components with autoimmune and autoinflammatory disorders illustrates that excessive inflammasome activity can be harmful. Therefore, inflammasome activation and activity are tightly regulated to avoid sterile inflammation. Inflammasome components such as NLRP3, caspase-11, and proIL-1β are expressed at relatively low levels, and priming with NFκB-activating inflammatory cytokines, TLR ligands, and other PAMPs is required for their mRNAs to be induced (Bauernfeind et al. 2011, Bulua et al. 2011, Kayagaki et al. 2011). In addition, type I interferon signaling is required for efficient activation of the AIM2 inflammasome by F. tularensis, although it is dispensable for activation of this inflammasome by mouse cytomegalovirus (Fernandes-Alnemri et al. 2010, Henry et al. 2007, Jones et al. 2010, Rathinam et al. 2010). Because AIM2 levels were not altered in F. tularensis-infected Irf3−/− and Ifnar−/− cells (Fernandes-Alnemri et al. 2010), type I interferon signals were proposed to enhance phagosomal digestion and cytosolic release of microbial DNA (Fernandes-Alnemri

et al. 2010). Further regulatory checkpoints involve human CARD-only proteins (COPs), such as ICEBERG, COP, INCA, and caspase12S , and PYD-only proteins (POPs), such as human cPOP1 and -2 (Lamkanfi & Dixit 2011). These molecules interfere with inflammasome assembly by scavenging ASC and caspase-1. Recent work also demonstrated that autophagy negatively regulates inflammasome activation, possibly by promoting accumulation of dysfunctional mitochondria and the release of mitochondrial DNA into the cytosol (Nakahira et al. 2011, Saitoh et al. 2008). Finally, the enzymatic activity of caspase-1 is directly regulated by the serpin proteinase inhibitor 9 (PI-9) and its two rodent homologs (Lamkanfi & Dixit 2011). The different checkpoint mechanisms above illustrate the importance of preventing unwarranted and disproportional activation of inflammasome effector pathways. It is thus not surprising that pathogens evolved different virulence mechanisms to modulate inflammasome activation to their benefit (Figure 4). A strategy often used by viruses is to mimic the mechanisms used by host cells to evade inflammasome activation. This theme is best illustrated by the cowpox virus PI-9 homolog cytokine response modifier A (CrmA) and similar serpins encoded by the orthopoxviruses vaccinia, ectromelia, and rabbitpox. In addition to the CrmA homologs SPI-1 and SPI-2, vaccinia produces soluble IL-18-binding proteins (vIL-18BPs) that prevent activation of the IL18 receptor as well as an IL-1β-neutralizing scavenger receptor named virus-encoded IL-1β receptor (vIL-1βR) (Lamkanfi & Dixit 2011). Myxoma virus M013L and Shope fibroma virus S013L also provide examples of how viral mimicry contributes to viremia. These viral POPs inhibit IL-1β production by interfering with its transcription while simultaneously scavenging ASC through their PYD domains to prevent proIL-1β maturation in inflammasomes (Rahman et al. 2009). Furthermore, Kaposi’s sarcoma-associated herpesvirus expresses Orf63, a NLRP1 homolog that contributes to virulence by preventing assembly www.annualreviews.org • Inflammasome Signaling in Disease

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Vaccinia vIL-1βR

Vaccinia Ectromelia Cowpox vIL-18BP IL-18

TLR

IL-1β IL-1R

IL-18R

Endosome Cowpox CrmA homologs: Rabbitpox CrmA Myxoma virus Serp2 Vaccinia virus SP1/2


KSHV Orf63 Nlrp3

PYD

NACHT

ASC

PYD

CARD

LRR

Active CASP11 CASP1 CARD

Caspase domain

Inflammasome

vPOPs: Myxoma virus M013L Shope fibroma virus S013L

NF-κB

Legionella pneumophila Poxviruses, other pathogens

Influenza NS1 Mycobacterium tuberculosis zmp1 Yersinia enterocolitica YopE, YopT Yersinia pseudotuberculosis YopK Pseudomonas aeruginosa ExoS, ExoU Francisella tularensis mviN

ProIL-1β, proIL-18

Figure 4 Virulence factors modulating inflammasome signaling. Certain viruses and bacterial pathogens express proteins that inhibit inflammasome assembly and activity. Cowpox CrmA and homologous serpins of myxoma and vaccinia virus bind and inhibit the enzymatic activity of caspase-1 directly. Orthopoxviruses also produce scavenger receptors that bind secreted IL-1β and IL-18. In addition, they express vPOPs that prevent inflammasome assembly by scavenging ASC. Similarly, KSHV Orf63 is a Nlrp1 decoy protein that prevents inflammasome assembly. Poxviruses, Legionella pneumophila, and other pathogens inhibit transcription of ASC, proIL-1β, and proIL-18 mRNA. Certain virulence factors encode enzymatic activities that modulate inflammasome activation. Examples are influenza NS1 protein; the Mycobacterium tuberculosis putative Zn2+ metalloprotease zmp1; the Yersinia effectors YopE, YopT, and YopK; the Pseudomonas aeruginosa virulence factors ExoS and ExoU; and Francisella tularensis mviN. Abbreviations: ASC, apoptosis-associated speck-like protein containing a CARD (caspase recruitment domain); CASP, caspase; CrmA, cytokine response modifier A; IL, interleukin; KSHV, Kaposi’s sarcoma-associated herpesvirus; LRR, leucine-rich repeat; NACHT, nucleotide-binding and oligomerization domain; NLR, Nod-like receptor; PYD, pyrin; TLR, Toll-like receptor; vPOP, PYD-only protein.

of the NLRP1 and NLRP3 inflammasomes (Gregory et al. 2011). In addition to using proteins mimicking host regulatory mechanisms, viruses have devised new ways to regulate inflammasome function. Human influenza A/PR/8/34 (H1N1) virus NS1 and baculovirus 152

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p35 are two examples of potent inflammasome inhibitors that lack apparent human paralogs (Lamkanfi & Dixit 2011). Some bacteria appear to use strategies aimed at preventing host recognition altogether by preventing their uptake and by


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masking their ligands. For example, the Yersinia pseudotuberculosis effector YopK prevents activation of the Nlrp3 and Nlrc4 inflammasomes by masking the bacterial type III secretion system (Lamkanfi & Dixit 2011). In addition, Yersinia enterocolitica YopE and YopT interfere with Rho GTPases to prevent cytoskeletal reorganizations and inflammasome assembly. Pathogens such as L. pneumophila downregulate transcription of ASC to prevent inflammasome activation and to promote their replication in human monocytes (Abdelaziz et al. 2011). Other bacterial virulence factors encode enzymatic activity to interfere with inflammasome activation. For example, P. aeruginosa exoenzyme U (ExoU) is a phospholipase that inhibits Nlrc4 inflammasome-driven secretion of IL-1β and IL-18, whereas the effector ExoS inhibits caspase-1 activation through its ADPribosyl transferase activity (Galle et al. 2008, Sutterwala et al. 2007). Finally, F. tularensis dampens AIM2 inflammasome-mediated IL-1β secretion and macrophage pyroptosis with its putative lipid II flippase mviN, whereas Mycobacterium tuberculosis inhibits activation of the Nlrp3 inflammasome using the putative Zn2+ metalloprotease zmp1 (Master et al. 2008, Ulland et al. 2010).

CONCLUSIONS AND PERSPECTIVES Step by step, our understanding of inflammasomes has made a giant leap in the past decade.

The appreciation that caspase-1 activation is not regulated by a single pathway, but instead is governed by a multitude of cytosolic protein complexes that are engaged in a highly regulated manner, has revolutionized our understanding of innate immune processes. Moreover, it has fueled our understanding of the mechanisms underlying autoinflammatory disorders such as CAPS and familial Mediterranean fever. However, many important questions remain to be answered, including how host cells decide which inflammasome to activate under particular conditions and how inflammasome signaling is intertwined with other innate and adaptive immune pathways. Undoubtedly, the roles of caspase-1 and caspase-11 and their relative contributions to infectious and autoinflammatory disorders are additional focal topics for inflammasome research in coming years. In addition, the precise mechanisms by which these inflammatory caspases initiate pyroptotic cell death and mediate unconventional protein secretion require further dissection. Answering these and other questions will surely expand the scope of ailments to which aberrant inflammasome signaling contributes. As the field moves forward, we expect to see increased application to human disease models. In addition to strategies targeting inflammatory caspases, clinical translation of this newly gained knowledge may unveil novel promising targets for therapeutic intervention in infectious, autoinflammatory, and autoimmune diseases.

DISCLOSURE STATEMENT V.M.D. is an employee of Genentech, Inc.

ACKNOWLEDGMENTS The authors apologize to those whose citations were omitted owing to space limitations. We thank Dr. Lieselotte Vande Walle for help with graphics. M.L. is supported by European Union Marie-Curie grant 256432, ERC Grant 281600, and grants G030212N, 1.2.201.10.N.00, and 1.5.122.11.N.00 from the Fund for Scientific Research–Flanders. www.annualreviews.org • Inflammasome Signaling in Disease

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Shi Y. 2004. Caspase activation: revisiting the induced proximity model. Cell 117:855–8 Shimada K, Crother TR, Karlin J, Chen S, Chiba N, et al. 2011. Caspase-1 dependent IL-1β secretion is critical for host defense in a mouse model of Chlamydia pneumoniae lung infection. PLoS ONE 6:e21477 Sims JE, Smith DE. 2010. The IL-1 family: regulators of immunity. Nat. Rev. Immunol. 10:89–102 Sutterwala FS, Mijares LA, Li L, Ogura Y, Kazmierczak BI, Flavell RA. 2007. Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome. J. Exp. Med. 204:3235–45 Sutterwala FS, Ogura Y, Szczepanik M, Lara-Tejero M, Lichtenberger GS, et al. 2006. Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity 24:317–27 Suzuki T, Franchi L, Toma C, Ashida H, Ogawa M, et al. 2007. Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLoS Pathog. 3:e111 Takagi H, Kanai T, Okazawa A, Kishi Y, Sato T, et al. 2003. Contrasting action of IL-12 and IL-18 in the development of dextran sodium sulphate colitis in mice. Scand. J. Gastroenterol. 38:837–44 Takeuchi O, Akira S. 2010. Pattern recognition receptors and inflammation. Cell 140:805–20 Tamura K, Fukuda Y, Sashio H, Takeda N, Bamba H, et al. 2002. IL18 polymorphism is associated with an increased risk of Crohn’s disease. J. Gastroenterol. 37(Suppl. 14):111–16 Tamura T, Yanai H, Savitsky D, Taniguchi T. 2008. The IRF family transcription factors in immunity and oncogenesis. Annu. Rev. Immunol. 26:535–84 Taylor RC, Cullen SP, Martin SJ. 2008. Apoptosis: controlled demolition at the cellular level. Nat. Rev. Mol. Cell Biol. 9:231–41 Terra JK, Cote CK, France B, Jenkins AL, Bozue JA, et al. 2010. Cutting edge: resistance to Bacillus anthracis infection mediated by a lethal toxin sensitive allele of Nalp1b/Nlrp1b. J. Immunol. 184:17–20 Thomas PG, Dash P, Aldridge JR Jr, Ellebedy AH, Reynolds C, et al. 2009. The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1. Immunity 30:566–75 Tian X, Pascal G, Monget P. 2009. Evolution and functional divergence of NLRP genes in mammalian reproductive systems. BMC Evol. Biol. 9:202 Toma C, Higa N, Koizumi Y, Nakasone N, Ogura Y, et al. 2010. Pathogenic Vibrio activate NLRP3 inflammasome via cytotoxins and TLR/nucleotide-binding oligomerization domain-mediated NF-κB signaling. J. Immunol. 184:5287–97 Trombetta ES, Parodi AJ. 2003. Quality control and protein folding in the secretory pathway. Annu. Rev. Cell Dev. Biol. 19:649–76 Tschopp J, Schroder K. 2010. NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nat. Rev. Immunol. 10:210–15 Ulland TK, Buchan BW, Ketterer MR, Fernandes-Alnemri T, Meyerholz DK, et al. 2010. Cutting edge: mutation of Francisella tularensis mviN leads to increased macrophage absent in melanoma 2 inflammasome activation and a loss of virulence. J. Immunol. 185:2670–74 Villani A-C, Lemire M, Fortin G, Louis E, Silverberg MS, et al. 2009. Common variants in the NLRP3 region contribute to Crohn’s disease susceptibility. Nat. Genet. 41:71–76 Walev I, Reske K, Palmer M, Valeva A, Bhakdi S. 1995. Potassium-inhibited processing of IL-1β in human monocytes. EMBO J. 14:1607–14 Wang S, Miura M, Jung YK, Zhu H, Li E, Yuan J. 1998. Murine caspase-11, an ICE-interacting protease, is essential for the activation of ICE. Cell 92:501–9 Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM. 2006. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24:677–88 West AP, Koblansky AA, Ghosh S. 2006. Recognition and signaling by Toll-like receptors. Annu. Rev. Cell Dev. Biol. 22:409–37 Wickliffe KE, Leppla SH, Moayeri M. 2008. Anthrax lethal toxin-induced inflammasome formation and caspase-1 activation are late events dependent on ion fluxes and the proteasome. Cell. Microbiol. 10:332– 43 Wright EK, Goodart SA, Growney JD, Hadinoto V, Endrizzi MG, et al. 2003. Naip5 affects host susceptibility to the intracellular pathogen Legionella pneumophila. Curr. Biol. 13:27–36


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www.annualreviews.org • Inflammasome Signaling in Disease

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Annual Review of Cell and Developmental Biology


Volume 28, 2012

Contents A Man for All Seasons: Reflections on the Life and Legacy of George Palade Marilyn G. Farquhar p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1 Cytokinesis in Animal Cells Rebecca A. Green, Ewa Paluch, and Karen Oegema p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p29 Driving the Cell Cycle Through Metabolism Ling Cai and Benjamin P. Tu p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p59 Dynamic Reorganization of Metabolic Enzymes into Intracellular Bodies Jeremy D. O’Connell, Alice Zhao, Andrew D. Ellington, and Edward M. Marcotte p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p89 Mechanisms of Intracellular Scaling Daniel L. Levy and Rebecca Heald p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 113 Inflammasomes and Their Roles in Health and Disease Mohamed Lamkanfi and Vishva M. Dixit p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 137 Nuclear Organization and Genome Function Kevin Van Bortle and Victor G. Corces p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 163 New Insights into the Troubles of Aneuploidy Jake J. Siegel and Angelika Amon p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 189 Dynamic Organizing Principles of the Plasma Membrane that Regulate Signal Transduction: Commemorating the Fortieth Anniversary of Singer and Nicolson’s Fluid-Mosaic Model Akihiro Kusumi, Takahiro K. Fujiwara, Rahul Chadda, Min Xie, Taka A. Tsunoyama, Ziya Kalay, Rinshi S. Kasai, and Kenichi G.N. Suzuki p p p p p p p p 215 Structural Basis of the Unfolded Protein Response Alexei Korennykh and Peter Walter p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 251

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The Membrane Fusion Enigma: SNAREs, Sec1/Munc18 Proteins, and Their Accomplices—Guilty as Charged? Josep Rizo and Thomas C. Sudhof ¨ p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 279 Diversity of Clathrin Function: New Tricks for an Old Protein Frances M. Brodsky p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 309 Multivesicular Body Morphogenesis Phyllis I. Hanson and Anil Cashikar p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 337


Beyond Homeostasis: A Predictive-Dynamic Framework for Understanding Cellular Behavior Peter L. Freddolino and Saeed Tavazoie p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 363 Bioengineering Methods for Analysis of Cells In Vitro Gregory H. Underhill, Peter Galie, Christopher S. Chen, and Sangeeta N. Bhatia p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 385 Emerging Roles for Lipid Droplets in Immunity and Host-Pathogen Interactions Hector Alex Saka and Raphael Valdivia p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 411 Second Messenger Regulation of Biofilm Formation: Breakthroughs in Understanding c-di-GMP Effector Systems Chelsea D. Boyd and George A. O’Toole p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 439 Hormonal Interactions in the Regulation of Plant Development Marleen Vanstraelen and Eva Benková p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 463 Hormonal Modulation of Plant Immunity Corné M.J. Pieterse, Dieuwertje Van der Does, Christos Zamioudis, Antonio Leon-Reyes, and Saskia C.M. Van Wees p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 489 Functional Diversity of Laminins Anna Domogatskaya, Sergey Rodin, and Karl Tryggvason p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 523 LINE-1 Retrotransposition in the Nervous System Charles A. Thomas, Apuã C.M. Paquola, and Alysson R. Muotri p p p p p p p p p p p p p p p p p p p p p p p 555 Axon Degeneration and Regeneration: Insights from Drosophila Models of Nerve Injury Yanshan Fang and Nancy M. Bonini p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 575 Cell Polarity as a Regulator of Cancer Cell Behavior Plasticity Senthil K. Muthuswamy and Bin Xue p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 599 Planar Cell Polarity and the Developmental Control of Cell Behavior in Vertebrate Embryos John B. Wallingford p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 627

Contents

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The Apical Polarity Protein Network in Drosophila Epithelial Cells: Regulation of Polarity, Junctions, Morphogenesis, Cell Growth, and Survival Ulrich Tepass p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 655 Gastrulation: Making and Shaping Germ Layers Lila Solnica-Krezel and Diane S. Sepich p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 687 Cardiac Regenerative Capacity and Mechanisms Kazu Kikuchi and Kenneth D. Poss p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 719


Paths Less Traveled: Evo-Devo Approaches to Investigating Animal Morphological Evolution Ricardo Mallarino and Arhat Abzhanov p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 743 Indexes Cumulative Index of Contributing Authors, Volumes 24–28 p p p p p p p p p p p p p p p p p p p p p p p p p p p 765 Cumulative Index of Chapter Titles, Volumes 24–28 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 768 Errata An online log of corrections to Annual Review of Cell and Developmental Biology articles may be found at http://cellbio.annualreviews.org/errata.shtml

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