The multifaceted link between inflammation and ... - Wiley Online Library

Received: 1 September 2017

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Accepted: 3 January 2018

DOI: 10.1002/jcp.26479

REVIEW ARTICLE

The multifaceted link between inflammation and human diseases Peramaiyan Rajendran1 | Ya-Fang Chen2,3 | Yu-Feng Chen4 | Li-Chin Chung5 | Shanmugam Tamilselvi1 | Chia-Yao Shen6 | Cecilia Hsuan Day6 | Ray-Jade Chen7 | Vijaya P. Viswanadha8 | Wei-Wen Kuo9 | Chih-Yang Huang1,10,11 1 Graduate

Institute of Basic Medical Science, China Medical University, Taichung, Taiwan

Increasing reports on epidemiological, diagnostic, and clinical studies suggest that

2 Department

dysfunction of the inflammatory reaction results in chronic illnesses such as cancer,

of Obstetrics and Gynecology, Taichung Veteran's General Hospital, Taichung, Taiwan

3 Division

of Cardiology, China Medical University Hospital, Taichung, Taiwan

4 Section

of Cardiology, Yuan Rung Hospital, Yuanlin, Taiwan

5 Department

of Hospital and Health Care Administration, Chia Nan University of Pharmacy and Science, Tainan County, Taiwan

6 Department

of Nursing, MeiHo University, Pingtung, Taiwan

7 Department

of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

8 Department

of Biotechnology, Bharathiar University, Coimbatore, India

arthritis, arteriosclerosis, neurological disorders, liver diseases, and renal disorders. Chronic inflammation might progress if injurious agent persists; however, more typically than not, the response is chronic from the start. Distinct to most changes in acute inflammation, chronic inflammation is characterized by the infiltration of damaged tissue by mononuclear cells like macrophages, lymphocytes, and plasma cells, in addition to tissue destruction and attempts to repair. Phagocytes are the key players in the chronic inflammatory response. However, the important drawback is the activation of pathological phagocytes, which might result from continued tissue damage and lead to harmful diseases. The longer the inflammation persists, the greater the chance for the establishment of human diseases. The aim of this review was to focus on advances in the understanding of chronic inflammation and to summarize the impact and involvement of inflammatory agents in certain human diseases.

9 Department

of Biological Science and Technology, China Medical University, Taichung, Taiwan

10 School

of Chinese Medicine, China Medical University, Taichung, Taiwan

KEYWORDS

arthritis, atherosclerosis, cancer, inflammation, neurological disorders

11 Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan

Correspondence Chih-Yang Huang, PhD, Graduate Institute of Basic Medical Science, Graduate Institute of Chinese Medical Science, China Medical University and Hospital, No. 91, Hsueh-Shih Road, Taichung 404, Taiwan. Email: [email protected] Wei-Wen Kuo, PhD, Department of Biological Science and Technology, China Medical University, No. 91, Hsueh-Shih Road, Taichung 404, Taiwan. Email: [email protected]

J Cell Physiol. 2018;1–14.

wileyonlinelibrary.com/journal/jcp

© 2018 Wiley Periodicals, Inc.

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1 | INTRODUCTION

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recruit macrophages to confined locales of inflammation and specifically activate a different signal transduction cascade and translation elements

Extensive physiological changes in cellular and molecular components

related to aggravation (Cekici et al., 2014).

are reported in the comprehensive process of inflammation. Controlled inflammation is an essential process required for wound healing and tissue repair and also for defense against invading foreign pathogens (Sethi, Shanmugam, Ramachandran, Kumar, & Tergaonkar, 2012). The goal of inflammation is to limit and destroy the causes of cell damage, clear and/or absorb necrotic cells and tissues, and begin tissue repair. Inflammation has been categorized into two discrete types: acute and chronic inflammation (Figure 1) (Egger, 2012 #9). Acute inflammation is self-restricting, yet drawn out attention because it is useful to the host to repair damaged cells in numerous illnesses and diseases. Chronic inflammation has generally been connected with diseases, such as diabetes, rheumatoid joint pain, atherosclerosis, multiple sclerosis, Alzheimer's disease and tumors (Baker, Hayden, & Ghosh, 2011). Direct penetration of many mononuclear immune cells, such as monocytes, lymphocytes, macrophages, and plasma cells, as well as the production of inflammatory cytokines, leads to chronic inflammation. Chronic inflammation is known to play a critical role in human diseases (Cekici, Kantarci, Hasturk, & Van Dyke, 2014). In general, both pro- and anti-inflammatory signaling pathways interact in the normal inflammatory process. An increasing number of pro- or anti-inflammatory biomarkers for measuring metainflammation have been newly identified (Ouchi, Parker, Lugus, & Walsh, 2011), and life-style related stimulants such as nutrition and behavior have been reported to be related with inflammation (Egger & Dixon, 2009). These inducers are not only associated with practices connected to current ways of life but are encouraged by postindustrial situations, for instance, poor nourishment, dormancy, deficient rest, and stress (Mishra, Neupane, Preen, Kallestrup, & Perry, 2015). Individual's responses to these situations (Mazzoli-Rocha, Fernandes, Einicker-Lamas, & Zin, 2010), transportation-related air quality (Alexeeff et al., 2011), endocrine-disruptingchemicals (EDCs) called obesogens, (Neel & Sargis, 2011), social and financial conditions that produce imbalance and monetary frailty (Elovainio et al., 2010), and also the connections among disparity and race/ethnicity, which suggest that labor results are more malicious in more established norms of certain denied racial/ethnic gatherings (Egede, 2006). These ways of life and situations facilitated to develop a classification of inducers that can be called “anthropogenic factors” due to their man-made beginning and potential impact on well-being. Anthropogenic factors are characterized here as man-made situations and their by-products, as well as man's way of life, that are supported by these situations. In addition, some of these have organic impacts that might be adverse to human well-being (Figure 1) (Egger, 2012). In pathological inflammatory progression, leucocytes, monocytes, macrophages, lymphocytes, and other protective cells are initially

2 | PRO-IN FL AMMA TORY CYT OK I NES Cytokines are small proteins that help immune cells to communicate; they are emitted from immune cells to reach a pathogen or a damagerelated atomic pattern with an antigen (Arango Duque & Descoteaux, 2014). Numerous cells of the innate and adaptive immune systems discharge cytokines, which enact or suppress the action of other immune cells by binding with particular receptors on these cells. Cytokines help to control all immune processes and have a purpose in every single process; they affect the link among humoral and cellular immunity and restrict the development of many immune cells. Cytokines include chemokines, interferons, interleukins, and tumor necrosis factors (Spiering, 2015). Chemokines exploit the receptors of leucocytes, which promote movement toward the source of the chemokines, and immune cells. Interferons (IFNs) are released by host cells during pathogenic infections, or during the presence of lethal proteins; they bind to and enact particular receptors on neighboring cells. This initiation prompts an expanded interpretation of the qualities of proteins that expand the cells' imperviousness to viral disease. IFNs also limit the initiation of B cells and the addition of the cytotoxicity of NK cells (Wang, Erbe, Hank, Morris, & Sondel, 2015). Interferons are represented by three distinct classes (α, β, and γ) and two types. Type I interferon (IFNalpha and IFN-beta) is secreted by virus-infected cells while type II, immune or gamma interferon (IFN-gamma) is mainly secreted by T cells, natural killer (NK) cells, and macrophages. Interleukins (ILs) are produced by leucocytes, lymphocytes, and even non-immune cells (in a few conditions) (Spiering, 2015). ILs incorporate cytokines and chemokines together. For example, low convergences of these proteins mostly encourage confined correspondence among leucocytes during inflammation and advance the development of chemokines to recruit extra immune cells. At elevated concentrations, some ILs (IL-1) enter the blood stream and act as endocrine hormones, producing fever and stimulating production of immune proteins in the liver (Spiering, 2015). Tumor necrosis factor α (TNFα) is a noteworthy pro-inflammatory cytokine. It is normally generated by macrophages and promotes inflammation during infection and in dysregulated immune responses, for example, in degenerative ailments (e.g., joint pain). Through binding and activating its particular cell receptor (TNFR), TNF-α activates few transcription factors, such as nuclear factor-κB, which upregulates the expression of pro-inflammatory genes. Furthermore, TNF-α activates cell passage and necrosis in some cell sorting processes (Sedger & McDermott, 2014).

activated. At this point, the cells are recruited to the site of damage that causes the release of reactive oxygen species (ROS) which is

3 | I NF L A M M A T I O N I N C A N C E R

harmful to macromolecules including DNA. In the meantime, these inflammatory cells also create many inflammatory mediators, for

The relationship between tumors and inflammation is not new and was

example, cytokines, chemokines, and prostaglandins. These additionally

initially proposed by Virchow in 1863; recently, it has been revisited by

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FIGURE 1 Conservative inflammation initiated by microbial antigens and metainflammation caused by inorganic anthropogenic factors and the pro- or anti-inflammatory effects of a variety of inducers. (a) Anti-inflammatory inducers associated with human activity have occurred since at least the Neolithic age. Pro-inflammatory inducers have mostly (except for smoking) been a part of the human environment only since the industrial revolution. Anthropogenic factors are defined as man-made environments and the by-products, behaviors, and/or lifestyles encouraged by those environments, some of which have biological effects that may be detrimental to human health. (b) Representation of the disparity between conventional inflammation (represented as the red eye), initiated by a microbial antigen or injury, and metainflammation, which is caused by inorganic anthropogenic factors

Frances Balkwill and Alberto Mantovani (Raposo, Beirao, Pang,

2012). Inside the tumor microenvironment, a system of different

Queiroga, & Argyle, 2015). Virchow proposed that an inflammatory

expert pro-inflammatory mediators participates in a perplexing

state advances the cell pathways that drive the inflammation and

signaling process that encourages extravasations of tumor cells

improvement of carcinogenesis (Demaria et al., 2010; Sethi et al.,

through the stroma, which consequently promotes the movement of

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tumor (Colotta, Allavena, Sica, Garlanda, & Mantovani, 2009; Dai

macrophages and other leucocytes, produce a large amount of

et al., 2017). The connection between inflammation and cancer

reactive oxygen and nitrogen species to fight infections (Mittal,

seems to occur via two pathways (Guven Maiorov, Keskin, Gursoy,

Siddiqui, Tran, Reddy, & Malik, 2014). Nevertheless, in constant

& Nussinov, 2013) 1) Intrinsic; and 2) Extrinsic inflammation

tissue damage and cell multiplication, the perseverance of these

pathways (Figure 2a). Intrinsic inflammation is initiated by

infection-battling representatives is harmful. They may form

transformations that prompt the activation of oncogenes and

mutagenic operators, for example, peroxynitrite, which responds

inactivation of tumor suppressor (the tumor-promoting part). In

to and causes source transformations in multiplying epithelial and

extrinsic pathway, infection or inflammation occurs before

stromal cells (Fulton, Loveless, & Heppner, 1984; Maeda & Akaike,

malignancy and promotes the risk of cancer (the tumor-initiating

1998). TNF-α may be released by macrophages and T-lymphocytes,

part) (Mantovani, Allavena, Sica, & Balkwill, 2008). There are

and the macrophage migration inhibitory factor (MIF) aggravates

various aspects of inflammation leading to the initiation of

DNA damage (Bloom & Al-Abed, 2014). Relocation of inhibitory

malignancy: 1) Pathogenic infections directly related to cancer,

factors weaken p53-subordinate defensive reactions and, in this

for example, feline leukemia virus (FeLV) (Beatty, 2014) and

manner, cause the aggregation of oncogenic changes (Candido &

Helicobacter pylori producing mucosa-associated lymphoid tissue

Hagemann, 2013).

(MALT) lymphoma in humans (De Falco et al., 2015); 2) chronic

The migration inhibitory issue additionally contributes to tumori-

inflammation promoted by immunity-mediated diseases, such as

genesis via Rb-E2F pathway (Conroy, Mawhinney, & Donnelly, 2010).

inflammatory bowel diseases (IBDs) and colon cancer (Frances-

In ileocolitis-related mouse cancer model, the high vulnerability to

cone, Hou, & Grivennikov, 2015); 3) subclinical manifestations can

inflammation and cancer in hydroperoxide (H2O2)-scavenging en-

cause inflammation, for example, Inflammation caused due to

zyme-deficiency in mice revealed the strength of intracellular likewise

fatness (Obese) may lead to liver tumors (Calle & Kaaks, 2004);

H2O2 added to the tumor initiation (Liou & Storz, 2010). Early

and 4) carcinogens produced by the environment lead to

inflammation includes the recruitment of a wide variety of immune

inflammation which can also cause tumors for example, smoke

cells to inflamed destinations, the additional release of different pro-

pollution (Chon, McCartan, Kubicek, & Vail, 2012).

inflammatory cytokines and different operators. These molecules work

Macrophages are prevalent in chronic inflammation microenvi-

in a coordinating way to initiate an inflammatory responses

ronment (Brady, Chuntova, & Schwertfeger, 2016). Together

(Mogensen, 2009). Inflammation is a precisely planned process;

FIGURE 2 (a) Extrinsic and intrinsic pathways of inflammation involving immune and inflammatory cells in cancer. (b) Inflammatory mechanism of atherosclerosis

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nonetheless, the distortions in the apoptosis and phagocytosis of in

important for cell association in both disease and normal conditions

situ inflammatory cells may prompt uncertain chronic inflammation

(Doring, Pawig, Weber, & Noels, 2014). The malignant cells continu-

(Okada, 2002). Migration inhibitory factor may likewise protect

ously express CXCR4 and the level of expression of CXCR4 by primary

transformed cells from being in confinement with the tumor silencer

human tumors is associated with the degree to which metastasis to the

gene p53 (Kindt, Journe, Laurent, & Saussez, 2016; Nishihira, 2000).

lymph node occurs in colorectal, breast, liver and esophageal

The damaging aspects of inflammatory cells and molecules persist after

malignancies (Chatterjee, Behnam Azad, & Nimmagadda, 2014; Kaifi

the tumors have been formed and when inflammatory cells penetrate

et al., 2005; Lombardi et al., 2013).

into tumor destinations. They are included in the circumvention of

Malignant cells also express functional chemokine receptors, like

tumor cells from the host immune reaction or play a considerably more

CC-chemokine receptor 1 (CCR1), CCR7, CCR9, CCR10, CXCR1,

straightforward role to encourage angiogenesis, tumor development,

CXCR2, CXCR3, CXCR5, and CXCR7in an assortment of tissues and

invasion, and metastasis independently or by eliciting other effector

are involved particularly in organ metastasis (Sarvaiya, Guo, Ulasov,

molecules like matrix metalloproteinases (MMPs) (Smith & Kang,

Gabikian, & Lesniak, 2013), for example, the expression of CCR7

2013). Tumor cells may additionally elicit cytokines and chemokines to

corresponds with lymph-node metastasis and the expression of CCR9

provide an increased progression of tumor in an undermined host

with the metastasis of melanoma in the small intestine. Invasive

defense response (Grivennikov, Greten, & Karin, 2010). Within such a

melanoma cells express a large amount of the above receptors, which

generalized model, several transcription factors, enzymes, besides

reveals possible clarification on why melanomas are actively meta-

cytokines and chemokines, should be taken into widespread consid-

static (Fusi et al., 2012). Drugs that target cancer-related inflammation

eration for their critical regulatory functions through this complicated

are used to re-program a tumor-enhancing inflammatory penetration

process. NF-κB mediates the cells involving in inflammatory reactions

or to prevent such cells from moving to the tumor location.

(Lawrence, 2009) and, more critically, slows down the advancement of

Additionally, they may have the capacity to re-program a tumor-

chronic inflammation by modulating the apoptosis of inflammatory

promoting microenvironment into a tumor-preventing microenviron-

cells (Lu, Ouyang, & Huang, 2006). The proposed positive feedback

ment to support tumor-specific versatile immune reactions and to

loop that exists between NF-κB and cytokines, for example, TNF-α,

repress metastatic spread. This idea for reversing tumor-supporting

may trigger NF-κB as an important controller of the entire system

inflammation could be the beginning of an exciting new era for

(Lawrence, 2009).

anticancer treatments (Garg, Maes, van Vliet, & Agostinis, 2015).

In addition, this putative feedback loop may partially be the reason for the persistent and prevalent existence of all these signaling molecules in inflammatory tissues and results in the enhancement of

4 | I NFLAM M ATI ON I N HEART DI SEAS E S

their effects in cancer development. In recent time, few reviews have gained ground in describing the role of NF-κB in connecting

Atherosclerosis is a chronic inflammatory disease and the main source

inflammation and cancer. These reviews showed that NF-κB is an

of myocardial inflammation (das Gracas Coelho de Souza et al., 2016).

anti-apoptotic effector in the tumor enhancement period of inflam-

Atherosclerotic animal models have shown to produce increased

mation-related malignancy, which ensures transformed cells by more

monocytes that are different from healthy ones (Chavakis, Preissner, &

than a few endogenous apoptotic factors (Elmore, 2007). The

Santoso, 2003), which prompts an enhanced post-myocardial infarc-

regulatory function of NF-κB appeared via its downstream particles

tion inflammatory reaction characterized by increased serum cyto-

like iNOS, COX-2, and HIF-1α. These particles themselves are

kines, increased recruitment and protection of inflammatory cells in

pleiotropic in inflammation and cancer and are thus potential focal

the infarct and expanded protease movement in the myocardium

points of the connections between inflammation and tumors (Reuter,

(Granger, Rodrigues, Yildirim, & Senchenkova, 2010). This renowned

Gupta, Chaturvedi, & Aggarwal, 2010). Various studies have shown

pro-inflammatory state has important functional significances. For

that different types of inflammation-related cytokines, including IL-6,

instance, elevated levels of circulating monocytes following myocar-

are related to carcinogenesis or cancer progression (Colotta et al.,

dial infection are associated with decreased functional recovery and

2009; Yu, Pardoll, & Jove, 2009). Activation of STAT3, which is found

unfavorable left ventricular (LV) remodeling (Dutta & Nahrendorf,

downstream of IL-6, appears to be an imperative step in the promotion

2015; Fang, Moore, Dart, & Wang, 2015). Increased serum cytokines

and progression of different genes related to carcinogenesis and

are also connected with higher progression of heart failure (Azzam

cancer progression including expansion, angiogenesis, invasion, and

et al., 2017; Cocco, Jerie, Amiet, & Pandolfi, 2017). In addition to

metastasis (Jones et al., 2016). Chemokine receptors and their ligands

compromised pump function, prominent post-MI inflammation may

influence the development of cells in inflammation and tumorogenesis

impact electrophysiological remodeling and the susceptibility to

in addition to that they keep up tissue homeostasis by influencing cell

arrhythmia through the actions of inflammatory cytokines and

motility, proliferation, and survival (Mantovani et al., 2008). In regard

proteases such as interleukin-1β (IL-1β) and matrix metalloprotei-

to transformation, many cells begin to express chemokine receptors

nase-7 (MMP-7). Together, these factors have been exposed to

and consequently utilize chemokines to facilitate their migration to,

degrade connexin-43 (Cx43) after MI, which slows down the

and survival at, locales that are far away from the original tumor

conduction and increases the propensity for arrhythmia (De Jesus

(Balkwill, 2004). CXCR4 and its ligand CXCL12 are reported to be very

et al., 2015; Lindsey & Zamilpa, 2012; Patel & Blazing, 2013). At least

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two subsets of monocytes have been described in humans and mice.

atherogenesis through the advancing of the outflow of cytokines

Mouse Ly-6C high monocytes, which are similar to CD14 high CD16

and adhesion particles and the relocation and mitogenesis of vascular

−human blood monocytes express high levels of the chemokine

smooth muscle and endothelial cells (Zhang, 2008). Chemokines need

receptor CCR2 and low levels of CX3CR1,and they rapidly permeate

to attach their coupled receptors to target cells to prompt cellular

injured tissues and force chronic inflammation (Mandl, Schmitz,

changes. Their receptors include a superfamily of 20 individuals, which

Weber, & Hristov, 2014). Circulating levels of classical monocytes,

have seven trans-layer loops combined with heterotrimeric G proteins

but not non-classical monocytes, were independently connected

(Kravchun, Narizhna, & Ryndina, 2014). The best-known individual

with cardiovascular events such as mortality, myocardial infarction,

from the CC chemokine family, monocyte chemoattractant protein-1

and stroke in a follow up study in two relatively large cohorts of

(MCP-1), which is named chemokine ligand CCL2 in the precise

coronary patients and in a randomly selected population (Ghattas,

classification, was observed to be highly associated with human

Griffiths, Devitt, Lip, & Shantsila, 2013). Furthermore, CD14 high

atherosclerotic scraped areas. Other CC family chemokines, for

CD16 intermediate monocytes were shown to independently predict

example, macrophage inflammatory protein-1α (MIP-1α)/CCL3 and

cardiovascular events in many subjects referred for elective

MIP-1β/CCL4, directly initiated ordinary T cell communication and

coronary angiography (Wildgruber et al., 2016). T-cells play a role

released (RANTES)/CCL5; additionally, various recently found chemo-

in atherosclerosis in the presence of the major histocompatibility

kines have been recognized in atherosclerotic areas (Nakajima et al.,

complex (MHC) class II cell surface receptor, HLA-DR and the

2002; Passos et al., 2009). Braunersreuther, Mach, and Steffens (2007)

existence of a huge number of CD3+ T cells occurs in atherosclerotic

showed in apolipoprotein E-deficient(ApoE−/−) mice that the spread

plaques in humans (Robertson & Hansson, 2006) and mice (Galkina

of atherosclerotic injuries connects well with an increased expression

et al., 2006). T lymphocytes are among the earliest cells to be

of pro-inflammatory chemokines and chemokine receptor in the aorta.

recruited into atherosclerotic plaques (Ammirati, Moroni, Magnoni,

Most current discoveries in animal models propose that blocking

& Camici, 2015). In reaction to the local milieu of cytokines, CD4+ T

chemokine/receptor cooperation could be another helpful approach

lymphocytes diverge into a Th1, Th2, or Th17 lineage. B cells in

for the treatment of atherosclerosis.

atherosclerosis were found primarily in the adventitia, and immuno-

People with diabetes have a higher risk of developing stroke,

globulin-like cells were found in atherosclerotic plaques (Campbell

myocardial infarction (MI), and claudicatio intermittens (Recarti, Sep,

et al., 2012). Despite the fact that specialists did not value the effect

Stehouwer, & Unger, 2015). The signs of atherosclerosis are also

of B cells on atherosclerosis at first, later reviews have assessed the

widespread in people suffering from diabetes (Jonelid et al., 2016).

role of B cells in coordinating the immune reaction in atherosclerosis

Morphologically, people with type 2 diabetes have reported to develop

(Figure 2b). An adaptive exchange of bone marrow from B cell–

more plaques and also a higher occurrence of plaque rupture, in

deficient mice into lethally irradiated Ldlr−/− mice resulted in up to a

contrast with people without diabetes (Cheng et al., 2016; Meier &

40% expanded injury measurement in parallel with the reduced

Thalmann, 2007). The reason for this highly damaging type of

production of anti-oxLDL antibodies. This lack of B cells did not

atherosclerosis is yet unclear and is often credited to expanded

appear to influence Th1 or Treg reactions, particularly because a

inflammatory activity in the vascular membrane. This hypothesis is

concurrent decrease in IFN-γ, IL-10, and TGF-β was observed

supported by histopathological discoveries of expanded plaque

(Galkina & Ley, 2009). Atherosclerosis in Apoe−/− mice is related to

penetration of macrophages and T-cells in carotid end arterectomy

expanded regular immune response titers to oxLDL. These IgM

and coronary autopsy studies in people with diabetes compared with

autoantibodies to oxLDL detect ox-PLs containing the phosphati-

their non-diabetic counterparts. Diverse components, for example,

dylcholine (PC) head group, and they block the binding and effects of

expanded endothelial oxidative anxiety; arrangement of cutting edge

oxLDL by macrophages in vitro (Galkina & Ley, 2009). The IgM

glycation end products (AGE)-adjusted structures; a glucose-depen-

antibodies found in atherosclerosis are basically and practically

dent enactment of the transcription nuclear factor of activated T-cells;

undefined compared to classic natural T15 anti-PC antibodies that

and the collection of triglyceride-rich lipoproteins and minimally dense

are made by B1 and backup zone B cells (Gronwall, Vas, & Silverman,

LDL in the vascular wall, have been implicated as the activators of this

2012). Vaccination with malondialdehyde (MDA) prompts the

enhanced vascular inflammatory activity (Cheng et al., 2013; Uranga &

development of antigen-particular Th2 cells, an increased generation

Keller, 2010). In people with obesity, the peri-vascular fat tissue adds

of IL-5, the noncognate incitement of B1 cells, and the accordingly

inflammation inside some of the vessels by emitting atherogenic

more generation of these antibodies (Jan et al., 2011). Master

cytokines. Macrophages invading visceral fat vary in conduct from

atherogenic cytokines, for example, tumor necrosis factor a (TNF-α),

those in the peripheral subcutaneous fat. Vital pro-inflammatory

interleukin (IL)-1, and IL-6, are emitted by macrophages, lympho-

cytokines, for example, TNF-α and IL-6, are unusual in macrophages of

cytes, common executioner cells, and vascular smooth muscle cells

instinctive fat. Increased levels of the pro-inflammatory adipokine

(Arango Duque & Descoteaux, 2014).

leptin in scLGI with IFNr and interleukin-6 (IL6) accumulation represent

TNF-α and IL-1 signaling is, for the most part, mediated by the p38

a connection between corpulence, atherosclerosis, and cardiovascular

mitogen-activated protein kinase (p38MAPK)/nuclear component

ailments. Leptin likewise contributes in immunity shifting to the Th1

kappa-light-chain-enhancer of the activated B-cell (NF-kB) pathway

type with a reduction in tryptophan levels in increased stomach

(Yang et al., 2014), and this provides all the requirements for

adiposity (Delmastro-Greenwood & Piganelli, 2013). Enzymatic

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degradation of abdominal fat by activated macrophages results in this

receptors on cells of the immune system and other cell types.

condition (Bhargava & Lee, 2012; Ramji & Davies, 2015; Tousoulis,

Pattern recognition receptors (PRRs) called toll-like receptors (TLRs)

Oikonomou, Economou, Crea, & Kaski, 2016). A small amount of

are one type of PAMP receptor. The response of certain TLRs to

adiponectin is discharged from the cells of the instinctive fat/

infection with viruses or bacteria have been reported. A total of 10

macrophage complex. The cytokines cause insulin resistance, endo-

different types of TLRs in humans have been identified, and each one

thelial damage and atherogenesis (Jung & Choi, 2014; Kang et al.,

can bind to a specific ligand.

2016). The key capacity of inflammation is proposed as an association

Restricted start of an intracellular signal cascade with various

between hazardous factors for atherosclerosis and its inconveniences.

impacts on processes like hemostasis, aggravation, and apoptosis,

The synergistic impacts of hypercholesterolemia and infection are

initiates the adaptive immune system. The regulation of cytokines,

shown in the progression of atherosclerosis. Air borne infections of the

chemokines, and other co-stimulatory mediators induces the activation

vascular endothelium might be involved in atherogenesis and even

of the adaptive immune system. The immune responses are initiated

result in coronary disorders. The DNA of microorganisms such as

with the stimulated CD4+ T cells and the upregulated and down-

Chlamydia pneumonia, Helicobacter pylori, and Herpesvirus have also

regulated mediators. Here, Th1- and Th2-like immune responses are

been identified in human atheromas. Additionally, periodontal diseases

typical. Furthermore, during the past several years, Th17-, Th21-, and

are found to correlate with markers of atherosclerosis and inflamma-

Treg T cell phenotypes and the corresponding immune responses have

tion (Assar, Nejatizadeh, Dehghan, Kargar, & Zolghadri, 2015; Camp-

been defined (Figure 3a). In contrast to chronic rhinosinusitis, the

bell & Rosenfeld, 2015). Studies have shown that an inflammation-

cytokines in the acute rhinosinusitis have not been investigated in detail

initiating population of monocytes/macrophages especially gathers in

(Scheckenbach & Wagenmann, 2016).

atherosclerotic plaques and generates pro-inflammatory cytokines.

TNF is a homotrimeric cytokine delivered as a membrane bound

Oxidized LDL (oxLDL) is an intense chemoattractant for inflammatory

protein, which is cleaved by proteases to release the soluble cytokine.

cells, particularly monocytes, and a few lymphocytes (Chen &

Together, the trans-layer and the soluble cytokine are organically

Khismatullin, 2015). The binding of oxLDL and the generation of

dynamic (Coondoo, 2011). TNF is produced by most of the cell types

chemotactic MCP-1 leads to inflammation initiation in the vascular

pertinent in arthritis pathogenesis, such as monocytes and macro-

endothelium. The lectin-like oxLDL receptor-1 (LOX-1) is upregulated

phages, dendritic cells, B cells, T cells, and fibroblasts, and is highly

in the endothelium and is accompanied by increase in blood pressure.

expressed in synovial fluids and in the synovial membrane of

When large amounts of oxLDL accumulate in the cells, they transform

Rheumatoid Arthritis (RA) patients. Its signal transduction occurs via

into foam cells. Macrophages collecting in the vascular intima cause a

two trans membrane receptors, TNFR1 and TNFR2. TNFR1 has been

fatty streak rich along with foam cells (Koskinas, Windecker, & Raber,

shown to mediate most of the pro-inflammatory signals of TNF. It

2016). Inflammatory- and immune responses are presently considered

activates fibroblasts, and in animal models, the appearance of TNFR1 on

to be more spatially and transiently dynamic than previously

fibroblasts is essential for the development of TNF-driven arthritis

suspected. The advancement of therapeutics focusing on chemokines

(Richter et al., 2012). IL-6, in addition to TNF, has become a cytokine that

and their receptors holds incredible promise for the treatment of

has been firmly established as a major player in RA. In RA animal models,

incurable cardiac illnesses sooner rather than later.

IL-6 deletion or treatment with anti-IL-6 agents ameliorated the disease, and

in

clinical

experiments

in

humans,

antibodies

to

the

IL-6 receptor and the ligand have also been shown to be successful

5 | INFLAMMATION IN ARTHRITIS

(Smith, 2010). IL-6 is a pleiotropic cytokine that acts on numerous cells of the immune system and the joint. It is an influential B cell activator

Inflammatory arthritis is the most common chronic inflammatory

and, in fact, was originally termed B cell stimulating factor 2 due to its

disease worldwide and is an important cause of disability due to its

growth promoting effects on plasmacytomas. It is also involved in T cell

critical nature in tissues (Anandarajah & Schwarz, 2009; Bluml,

polarization and has been shown to be important in the generation of

Redlich, & Smolen, 2014). Synovial inflammation is a precondition for

Th17 cells via STAT3 (Veldhoen, Hocking, Atkins, Locksley, & Stock-

the development of injury to the articular structures. In strong joints,

inger, 2006). It amplifies the initiation and activation of osteoclasts, and

the synovial membrane consists of a very thin lining layer of only a

the overexpression of IL-6 decreases osteoclast numbers in TNF-driven

few cells in thickness and a thin sublining of the lining layer, which

arthritis and joint injury in human RA (Smolen, Avila, & Aletaha, 2012).

faces the joint cavity and comprises fibroblast-like synoviocytes

Animal studies have identified IL-1 as a significant controller of

(FLS) of mesenchymal origin (type B cells) and macrophage-like

inflammatory arthritis. Blocking the cytokine or deficiency of IL-1

synoviocytes of myeloid origin (type A cells), whereas, the sub-lining

protects mice from almost all models of arthritis, and IL-1 was shown to

primarily comprises a network of sparsely populated fibroblasts and

be involved in presumably pathogenic events, such as cartilage injury,

connective tissue (Bluml et al., 2014). For immune defense, both the

osteoclast generation, and T cell activation and division, to name a few

innate and adaptive immunity networks are initiated in a signal-

(Bartok & Firestein, 2010; Bluml et al., 2014). However, clinical trials did

dependent manner. The innate immune system is initiated by

not meet expectations, which is why anakinra (an IL-1 receptor

pathogen-associated molecular patterns (PAMPs), which are com-

antagonist), as well as monoclonal antibodies to IL-1 or the IL-1

municated by particular pathogen classes that can activate PAMP

receptor and IL-1 blockade, currently play only a minor role in the

8

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FIGURE 3 Inflammatory mechanism of arthritis and the central nervous system. (a) The self-sustaining chronic inflammatory loop maintained through TLR activation in a variety of cells contributes to the chronic course of rheumatic disease. Activation of TLRs in rheumatic diseases can occur by microorganism-associated molecular patterns (MAMPs) such as lipopolysaccharides. (b) Inflammatory molecules released from vascular endothelial cells, leucocytes, astrocytes, microglial cells and neurons may affect neuronal functions in the cardiovascular center and induce sympatho excitation. Hypoxia and ROS production induced by abnormal inflammatory responses may also affect neuronal functions

treatment of RA, although anakinra is extremely successful in treating

Crohn's disease. These suggest that interleukin-23 could thus be

various periodic fever syndromes (Bluml et al., 2014).

considered as an early sign of gut inflammation in AS patients (Jacques

During studies of interleukin-23 receptor functional polymor-

et al., 2010).

phisms, new information regarding the normal pathogenesis of gut and

Data from animal models support a role of the Th17 subset in SpA.

joint inflammation in SpA was revealed by the investigation of the IL-

In B27/b2m-transgenic rats, a correlation was observed between B27

17 producing (Th17) lineage of T cells. Th17 cells are a newly found

misfolding and the resulting UPR and interleukin-23 upregulation.

effector T lymphocyte subset with fundamental pro-inflammatory

Furthermore, interleukin-23 was upregulated in the colon tissue from

qualities (Jacques, Elewaut, & Mielants, 2010). In the refinement of

these rats at the same time as the advancement of enterocolitis, and IL-

other effector T-cell subsets, Th17 cells express the interleukin-23

17 was upregulated in a similar model (DeLay et al., 2009).

receptor on their membrane and are reliant on this cytokine for their

Furthermore, an expanded recurrence of Th17 cells was accounted

survival and development (Jager & Kuchroo, 2010). Data on this

for in the TNFDARE mouse model (Li & Schwarz, 2003). Increased

captivating subset are continually developing. Expanded quantities of

levels of IL-17-producingCD4þ T cells were observed in the terminal

Th17 cells were added to the peripheral blood of spondyloarthritis

ileum of these mice in contrast with the controls, despite the fact that it

(SpA) and ankylosing spondylitis (AS) patients and compared to RA

is unclear whether IL-17 blockade can modify the ailment itself.

patients and solid controls (Lubrano & Perrotta, 2016; Smith & Colbert,

Nevertheless, current treatments modulate inflammatory causes and

2014). Wendling, Cedoz, Racadot, & Dumoulin, 2007) showed

are especially effective in repressing arthritis.

commonly reported serum levels in AS patients, whereas, Melis et al. (2010) showed that Th17 cytokines were pronounced in the joints of SpA patients, despite the fact that these authors did not see

6 | I N F L A M M A T I O N I N B R A IN D I S E A S E S

large differences in the serum and synovial fluid levels of IL-17 in nonSpA patients with fringe joint pain compared to the controls. In any

In central nervous system (CNS), degenerative movements are

case, as CCL20 was identified as a chemokine attractant in Th17 cells

described by morphological, anatomical, and effective changes during

(Krzysiek et al., 2000), Melis et al. indicated that synovial liquid CCL20

chronic and dynamic neuronal defects. Chronic neurodegenerative

levels were increased, in contrast with serum levels, suggesting a true

illnesses are characterized as hereditary, sporadic, and protein

chemotactic role for CCL20 in attracting this pathogenic T-cell subset

misfolding maladies, which are generally described by the decrease

to the SpA joint. A current report by Ciccia et al. (2009) showed that

of intellectual capacities, especially learning and memory. These

subclinical gut inflammation via chronic inflammation in AS was

illnesses include Alzheimer's disease (AD) and different dementias,

correlated with an overexpression of interleukin-23. This was not

transmissible spongiform encephalopathies (TSEs), amyotrophic hori-

related with the upregulation of IL-17, which is similar to the case in

zontal sclerosis (ALS), Parkinson's disease (PD), Huntington's disease

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9

(HD), and prion ailments. The causes related to neuronal degeneration

classical inflammation and thus adapt to immunosuppression following

remain unknown (Sochocka, Diniz, & Leszek, 2016). The use of

their engulfment by macrophages. In response, the macrophages

immuno-inflammatory control is one of the applicable procedures

upregulate the expression of the Th2 anti-inflammatory cytokine IL-

required in the pathogenesis of neurodegenerative issues. An innate

10, whereas they significantly down regulate the pro-inflammatory

and adaptive resistant reaction in the brain is firmly controlled in the

cytokines TNF-α, IL-1β, and IL-12. A number of subtypes of the M2

connection with the periphery. Immune initiation in the CNS

macrophage exist depending on the inflammatory agenda that is

dependably includes microglia and astrocytes, which contribute to

activated and required (Voll et al., 1997; Mantovani et al., 2004;

the control of homeostasis of the brain in non-neurotic conditions.

Orihuela, McPherson, & Harry, 2016). M2a or another macrophage is

Endothelial cells and perivascular macrophages are imperative to the

triggered by the cytokines IL-4 and IL-13, and these macrophages are

elucidation and proliferation of inflammatory signals in the CNS

specialized to carry out the immune response and the killing and

(DiSabato, Quan, & Godbout, 2016).

encapsulation of parasites. The M2b macrophage is activated by

An important inflammatory stimulus is lipopolysaccharide (LPS),

ligation of TLRs+immune complexes and the IL-1 receptor. This

which is a protein in Gram-negative microscopic organisms that

macrophage subset is primarily responsible for the immune regulation

stimulates the HPA axis to make CRF (corticotropin releasing factor).

and activation of the Th2 program. The M2c macrophage, which is

Despite the fact that the stress reaction is enacted by these stimuli, the

activated by cytokine IL-10, is primarily responsible for matrix

resultant physiological changes additionally prepare living organisms

deposition and tissue remodeling. Recently, a fourth and distinct

to develop diseases (Maniscalco, Kreisler, & Rinaman, 2012). Along

subtype, which is termed the M2d subset, has been identified. This

these lines, corticosteroids and catecholamines, which are the

subset is activated by IL-6 and is thought to aid in tumor metastasis and

significant stress hormones, start a reaction characterized by the

progression (Duluc et al., 2007). The primary cells responsible for the

generation of cytokines and intense stage reactants as in an

synthesis of these cytokines are eosinophils, basophils, CD4+Th2 cells,

inflammatory state. Subsequently, the provocative reaction is

and tumor cells. M2 macrophages downregulate the release of IL-1,

contained inside the stress response that is evoked by psychogenic

IFN-γ, IL-12, and TNF-α (Anthony, Rutitzky, Stadecker, & Gause, 2007;

signals (Black, 2002; Hsu & Yin, 2016). The coupling has clear survival

Duluc et al., 2007).

advantages for an animal occupied with or recovering from battle. The

In glioma tissue, macrophages/microglia can account for up to

immune system advanced from the inflammatory system and, similarly,

30% of the total lymphocytic infiltrate in the tumor mass (D'Andrea

is required for the protection of the host. The immune system also

et al., 1993; Kennedy et al., 2013). It is currently accepted that the

combined with the anxiety of the reaction, that is, the brain and the

macrophage and microglia populations established within glioma

immune system communicate in a negative feedback cycle (Chesno-

originate from different progenitor cell populations. Infiltrating

kova & Melmed, 2002; Rea, Dinan, & Cryan, 2016). A total

macrophages are derived from the bone marrow, whereas, microglia

inflammatory reaction causes the production of cytokines, for

are brain resident; they initiate from primitive progenitors in the yolk

example, IL-1, IL-6, and TNF, which circulate in the blood and

sac and move into the CNS during early embryo development (da

communicate with neurons inside the brain (Figure 3b). There are

Fonseca & Badie, 2013; Ginhoux et al., 2010). It has also been

various diverse courses by which a systemic inflammatory reaction

demonstrated, using parabiosis and experimental autoimmune

may communicate with the CNS (Perry & Teeling, 2013; Sankowski,

encephalomyelitis models, that circulating monocytes do not occupy

Mader, & Valdes-Ferrer, 2015). The beginning of the classical

the CNS unless the CNS is pre-conditioned with irradiation or the

inflammatory response is marked by the localization and succeeding

blood-brain barrier is allowed/damaged (Guilliams & Scott, 2017).

transformation of blood circulating monocytes into M1 macrophages.

Taken together, microglia are probably recruited to the glioma

The M1 macrophages are activated by cytokines produced by Th1

microenvironment at all stages of malignancy, whereas, a majority of

cells, such as IFN-γ and TNF-α, after the detection of pathogen-

the macrophages accumulate only after an insult or blood-brain barrier

associated molecular pattern molecules in the course of TLRs or C-type

breakdown when chronic type II inflammation is dominant in the

lectin receptors. Before activation, the M1 macrophage supports a

glioma microenvironment. The convertibility of macrophages from an

pro-inflammatory environment by releasing cytokines such as TNF-α,

M1 to an M2 polarized status is determined by factors produced by the

IL-1, IL-6, IL-12, IFN-γ, and IL-23. IL-12 stimulates IFN-γ production in

local glioma microenvironment. Certainly, secreted or displayed glioma

T lymphocytes and natural killer (NK) cells (Kyurkchiev et al., 2014).

factors are able to manipulate macrophage and microglial behavior that

Phenotypically, the M1 phenotype is associated with cell-mediated

supports tumor survival and growth. Inactive microglia are character-

cytotoxicity, tissue injury, and destruction. Thus, the presence of the

ized by a branchmorphology; they display widespread branched

M1 macrophage is counter-protective once the invading threat is

projections that support nonstop surveillance of the CNS microenvi-

neutralized and once tissue repair is in order. The resolution of the

ronment (Fumagalli, Perego, Pischiutta, Zanier, & De Simoni, 2015;

inflammatory response and conversion into wound restoration is

Galvao & Zong, 2013). Glioma cells exude solution immunomodulatory

facilitated by the M2 macrophage. One of the resolutions of the events

factors that suppress type I immune activity such as IL-10, IL-4, IL-6,

leading to immune-suppression and the establishment of type 2

TGF-β, and prostaglandin E2 (Qiu et al., 2011). The cytokines IL-10, IL-

inflammation is the apoptotic cell death of recruited neutrophils

4, and IL-6 are exposed to stimulate an M2 rounded morphology that is

(Kyurkchiev et al., 2014). The apoptotic neutrophils signal to stop

characteristic of activated microglia, whereas, the T helper Th 3

10

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cytokine, TGF-β, is known to inhibit microglial cell proliferation and the

microenvironment is that the normal genome of inflammatory/

appearance of pro-inflammatory cytokines in vitro(Qiu et al., 2011).

immune cells, which, unlike the cancer cell genome, is not subject to

Due to the dominant effect that glioma cells and their secreted factors

mutational and epigenetic changes that result in drug resistance.

present on the surrounding cells, it is likely that glioma-recruited

However, in most cases, anti-inflammatory therapy is not cytocidal on

microglia preferentially adopt an M2 phenotype. Studies that delineate

its own and needs to be combined with more conventional therapies

the interactions between glioma cells and macrophages/microglia are

that kill cancer cells. Despite such limitations, several anti-inflamma-

still warranted.

tory drugs have been found to reduce tumor incidence when used as prophylactics, as well as to slow down progression and reduce mortality when used as therapeutics, particularly in the case of

7 | THERAPEUTICS TARGETING PERSISTENT INFLAMMATION IN HUMAN DISEASES

sporadic colon cancer. Such drugs include COX2 inhibitors, aspirin, and anti-inflammatory steroids, such as dexamethasone. In addition to its well-documented preventive effects in colon cancer, aspirin reduces the incidence of breast cancer and reduces prostate cancer risk, but

Numerous common and deadly illnesses, including cancer, atheroscle-

only in individuals that carry a particular polymorphic allele at the

rosis, arthritis, and neurological diseases, have been associated with

lymphotoxin α locus, which specifies high lymphotoxin production

pathophysiological important inflammation components. In these

Such findings are of general importance because nonsteroidal anti-

diseases, the correct determinant of the inflammation activation is

inflammatory drugs (NSAIDs), such as aspirin, are not very specific and

obscure, and if known, it is difficult to cure. Despite the fact that there

usually have side effects that preclude their long-term administration

have been developments in the anti-inflammatory treatment of

except in high-risk individuals. Thus, prescreening for individuals with

chronic diseases primarily activated by inflammation dysregulation

high cancer risk that are more likely to benefit from such preventive

or autoimmunity, there are currently significant limits to the permitted

strategies should greatly improve the efficacy and utility of cancer

inflammation levels. Generally, the inflammation reaction is critical for

prevention (Grivennikov et al., 2010).

survival. As a result, excess compensatory pathways and the severity

Therapeutic agents and strategies are being devised to either

of the risks leading to the production of number of anti-inflammatory

interrupt or inhibit one or more of the pathogenic steps involved in the

medications. In atherosclerosis, which is a significant and informative

process of neovascularisation, and indeed blockade of angiogenesis

example of the tasks in this area. Sub-endothelial retention of

has been effective in many tumor models. It is not unreasonable to

apolipoprotein B containing lipoproteins triggers a maladaptive,

suggest that targeting the newly formed vasculature of the RA pannus,

nonresolving inflammatory response that drives atherogenesis (see

in combination with other therapies such as anti-TNF-α, may lead to a

the Review in this issue by Swirski and Nahrendorf) (Swirski &

more persistent reduction in pannus volume and hence modify disease

Nahrendorf, 2013; Tabas & Glass, 2013). Initial, the statin class of

progression. Blockade of angiogenesis in rats with collagen-induced

drugs are used in virtually all subjects at high risk for atherosclerotic

arthritis using TNP-470 was found not only to inhibit onset of arthritis,

disease. Thus, anti-inflammatory therapy would be used typically in

but also to suppress established disease, with a concomitant reduction

combination with statins and would have to show efficiency better

in circulating VEGF levels. More recently, specific antagonists of were

than that with statins alone, which themselves may have some anti-

used in a rabbit model resembling human RA, in which arthritis was

inflammatory effects (30). Second, although early use of anti-

induced by injection of ovalbumin and FGF2, and treatment consisted

inflammatory therapy might be most effective in combating athero-

of intra-articular injections of αVβ-33 antibody or control. Treatment

sclerosis before certain aspects of the pathology become irreversible,

with αVβ-33 antibody decreased vascularity in the arthritic synovium,

this would require a very long treatment period and may therefore

associated with a significant decrease in all arthritic parameters

have an unacceptable benefit:risk ratio. Equally, although the benefit:

including joint swelling and synovitis. More importantly, the beneficial

risk ratio might be most suitable for shorter-term treatment of

effects of angiogenesis inhibition were evident even in chronic, well-

progressive atherosclerosis, it is precisely in this situation that anti-

established disease (Paleolog & Fava, 1998).

inflammatory therapy would be least effective. In this situation, the

The blood–brain barrier is a complex network of vasculature

value may lie in avoiding the development of earlier lesions that are

comprised of a tight layer of capillary endothelial cells along with

known to coexist with advanced lesions (Tabas & Glass, 2013). In this

clusters of enzymes, efflux pumps, receptors, and transporters acting

context, investigators are beginning to ask whether drugs used for

in concert to limit access of molecules to the central nervous system.

chronic primary inflammatory diseases might be useful to prevent

However, if the molecules are permeabilized, they become distributed

atherosclerotic disease, and they have recently turned their attention

throughout the brain as a result of its rich vasculature. As stated earlier,

to DMARDs. The genetic and pharmacologic targeting of many

the major limitation in the treatment of neurological disease is the

individual inflammatory processes and molecules in mouse models of

inability to deliver drug molecules across the blood–brain barrier.

atherosclerosis leads to decreases in aortic atherosclerosis (Tabas &

Therefore, the main focus of research is the development of treatment

Glass, 2013). Understanding of the molecular etiology of cancer and

strategies targeting specific markers on the capillary endothelium

lay the foundations for the use of anti-inflammatory drugs in cancer

associated with the various pathologies. The targeting agents could be

prevention and therapy. One advantage of targeting the inflammatory

anti-bodies or substrates for receptors, or could be drug-loaded

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nanoparticles. Nanoparticles are typically characterized as colloidal drug delivery systems with a size measuring not more than 100 nm, and have significant potential for delivering drugs across the blood– brain barrier. After thorough investigation, nanotechnological administration has been found to be the most reliable mode of drug administration, given that the challenges of drug delivery to the brain are unmet by conventional therapeutics (Kanwar, Sriramoju, & Kanwar, 2012). Moreover, new advances are required regarding sympathetic inflammatory signaling and its connections to determine common pathways for the creation and improvement of new medications (Tabas & Glass, 2013).

8 | C ONC LU SI ON Chronic inflammation plays a vital role in a variety of human diseases, including coronary heart disease, diabetes, malignancy, and joint inflammation. Emerging laboratory and clinical statistics provide strong indication that inflammatory pathways contribute decisively to the pathogenesis of a number of chronic diseases associated with aging, lifestyle, and that these processes involve common pro-inflammatory mediators and regulatory pathways. By understanding the common mechanisms, and shared mechanisms that or chestrate the array of dysfunction of our various organ systems, we will be able to better predict susceptibility to disease and gauge target therapies. Fortunately, existence measures such as self-denial from a healthy diet, tobacco, and regular physical activity can often permit an individual to prevent off many of these inflammatory diseases, and lessen the likelihood that chronic diseases will limit a long and healthy life. A detailed understanding of the distinctive roles played by chronic inflammation is necessary to develop more successful and reliable medicines.

ORCID Chih-Yang Huang

http://orcid.org/0000-0003-2347-0411

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How to cite this article: Rajendran P, Chen Y-F, Chen Y-F, et al. The multifaceted link between inflammation and human diseases. J Cell Physiol. 2018;1–14. https://doi.org/10.1002/jcp.26479