These articles have been accepted for publication in the British Journal of Dermatology and are currently being edited and typeset. Readers should note that articles published below have been fully refereed, but have not been through the copy-editing and proof correction process. Wiley-Blackwell and the British Association of Dermatologists cannot be held responsible for errors or consequences arising from the use of information contained in these articles; nor do the views and opinions expressed necessarily reflect those of Wiley-Blackwell or the British Association of Dermatologists Accepted Date : 23-Sep-2012 Article type : Correspondence Impaired Notch signalling: the unifying mechanism explaining the pathogenesis of acne inversa Madam, there has been yet uncertainty about the origin of acne inversa (AI) (hidradenitis suppurativa). However, in 2010, Wang et al.1 found independent loss-offunction mutations in PSENEN, PSEN1, and NCSTN, the genes encoding essential components of the γ-secretase multiprotein complex. γ-Secretase is a transmembrane protease composed of four essential protein subunits: one catalytic presenilin (PSEN1) subunit and three cofactor subunits (presenilin enhancer 2 (PSENEN), nicastrin (NCSTN) and anterior pharynx defective 1 (APH1). Most recently, the pathogenic role of NCSTN and PSENEN mutations in familial AI has been confirmed. γ-Secretase is involved in the regulation of the canonical Notch signalling pathway. Intramembrane cleavage of Notch by γ-secretase releases the intracellular domain of Notch (NICD) that exhibits signalling activity in the nucleus (Figure 1). AI affects predominantly occluded skin areas that are rich in terminal hair follicles and apocrine glands. The canonical Notch pathway is required for hair follicle terminal differentiation and for postnatal hair cycle homeostasis.2,3 Sebaceous glands failed to form in γ-secretase-deficient mice.4 Remarkably, sebaceous gland number and volume are significantly reduced in uninvolved hair follicles from patients with AI.5 In Notch-deficient mice, hair follicles with defective terminal differentiation were replaced by epidermal cysts.6 Inhibition of Notch signalling resulted in inhibition of the hair growth cycle, conversion of hair follicles into cysts, and inhibition of sebaceous gland differentiation.7 Remarkably, epithelial cysts and squamous epithelium-lined structures are not an uncommon histological finding in lesional skin of patients with AI.8 AI is more frequently associated with other chronic autoinflammatory diseases like Crohn´s diseses or PAPA syndrome, which share Th17-driven immunopathology. IL-23, the important stimulus for the differentiation of naïve T-cells into Th17 cells, is
abundantly expressed by macrophages of lesional skin from patients with AI consistent with the detection of IL-17-producing helper T cells in dermal infiltrates of lesional skin.9 Th17 differentiation requires the exposure to TGF-β, IL-1β, IL-6, IL-21 and IL-23. Indeed, elevated levels of IL-1β, IL-23 and TNF-α have been observed in the skin of patients with AI.9,10 Thus, the cytokine composition of lesional skin appears to be able to promote Th17-driven autoinflammatory reactions. Recent evidence points to a crucial cross-regulation
between
Notch
macrophages.11
Intriguingly,
and
Notch
Toll-like signalling
receptor
(TLR)
suppresses
signalling
in
TLR4-triggered
proinflammatory macrophage cytokine expression by a negative feedback regulation.10 Impaired Notch signalling in AI may thus explain excessive proinflammatory cytokine production of macrophages (TNFα, IL-1β, IL-23), which activates Th17-mediated immune responses. A relative deficiency of IL-22 has been demonstrated in lesional skin of patients with AI,12 which underlines the role of impaired Notch signalling as the secretion of IL-22 by CD4+ T cells depends on activated Notch signalling.13 Furthermore, the reduction in the percentage of NK cells in patients with AI may again result from impaired Notch signalling as Notch induces the generation of functional NK cells, which is blocked by inhibition of γ-secretase.14,15 Smoking, obesity and occlusion are well known risk factors aggravating AI. Remarkably, it has been reported that smoking down-regulates Notch signalling in human airway epithelium.16 Suppression of Notch signalling by smoking may thus augment the pre-existent deficiency of Notch signal transduction in patients with AI. In obesity, visceral fat macrophages secrete excessive amounts of TNF-α and IL1β into the systemic circulation.17 TNF-α is a master regulator of proinflammatory cytokine production and thus augments the synthesis of IL-1β. Adipose tissue macrophage-derived cytokines most likely amplify tissue levels of proinflammtory cytokines in the skin of obese patients with AI. Obesity not only stimulates the release of proinflammatory cytokines, but enlarges the area of occluded intertriginous skin. Besides maintaining terminal epidermal differentiation and cell adhesion, Notch signalling sustains the epidermal barrier function and orchestrates communication between epithelial and immune compartments of the skin to prevent chronic Th17-driven inflammation.2,18 It is thus conceivable that epidermal barrier stress evoked by skin occlusion may further compromise aberrant Notch signalling in AI. Consecutively, autoinflammatory Th17-
driven signalling may preferentially induce the evolution of inflammatory lesions in occluded intertriginous areas of the skin exposed to increased barrier stress. Patients with AI exhibit a higher incidence of squamous cell carcinoma (SCC),19 which may not only be explained by high exposure to tobacco-derived carcinogens, but more reasonably by impaired Notch signalling. Notably, Notch acts as an epidermal tumour suppressor in SCC.7,20 After decades of aimless speculations, impaired Notch signalling now appears to explain all major pathogenic events in AI: 1) disturbed Notch-mediated keratinization of terminal hair follicles with epidermal cyst formation, impaired development of sebaceous glands and abnormal T-cell mediated immunity with deficient IL-22 secretion and especially impaired Notch-mediated suppression of the TLR/IL-23/Th17 axis thus promoting autoinflammatory Th17-driven reactions. Activated TLRs on macrophages stimulate the NALP3 inflammasome pathway, which fulfils the proteolytic processing of pro-IL-1β to it active form.21 The presented γ-secretase-Notch-TLRinflammasome pathway thus links AI to the family of inherited chronic autoinflammatory disorders, which exhibit a significant comorbidity with AI. Deficient Notch signalling explains the aggravation of AI by smoking, obesity, and skin occlusion as well as the increased disposition for SCC (Figure 2). New treatment strategies in AI have either 1) to restore deficient Notch signalling, 2) to mitigate immunological aberrations derived from deviated Notch signalling, and 3) to avoid aggravating factors, which further potentiate Th17-mediated immunopathology. The correction of aberrant Notch signalling in AI may help to ameliorate one of the most troublesome and disfiguring chronic inflammatory skin diseases, which should be regarded as an autoinflammatory terminal hair folliculitis of occluded skin areas primarily provoked by inadequate Notch signal transduction. B.C . Melnik1, G. Plewig2 1Department
of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, Sedanstrasse 115, D-49090 Osnabrück, Germany 2Clinic
and Policlinic for Dermatology and Allergology, University of Munich, Frauenlobstrasse 9-11, D-80337 München, Germany Correspondence: Bodo C. Melnik E-mail:
[email protected]
Conflicts of interest None declared References 1
Wang B, Yang W, Wen W et al. γ-secretase gene mutations in familial acne inversa. Science 2010; 330: 1065.
2
Blanpain C, Lowry WE, Pasolli HA et al. Canonical notch signaling functions as a commitment switch in the epidermal lineage. Genes Dev 2006; 20: 3022-35.
3
Lin HY, Kao CH, Lin KMC et al. Notch signaling regulates late-stage epidermal differentiation and maintains postnatal hair cycle homeostasis. PLoS ONE 2011; 6: e15842.
4
Pan Y, Lin MH, Tian X et al. γ-secretase functions through Notch signaling to maintain skin appendages but is not required for their patterning or initial morphogenesis. Dev Cell 2004; 7: 731-43.
5
Kamp S, Fiehn AM, Stenderup K et al. Hidradenitis suppurativa: a disease of the absent sebaceous gland? Sebaceous gland number and volume are significantly reduced in uninvolved hair follicles from patients with hidradenitis suppurativa. Br J Dermatol 2011; 164: 1017-22.
6
Demehri S, Kopan R. Notch signaling in bulge stem cells is not required for selection of hair follicle fate. Development 2009; 136: 891-6.
7 cancer 8
Watt FM, Estrach S, Ambler CA. Epidermal Notch signaling: differentiation, and adhesion. Curr Opin Cell Biol 2008; 20: 171-9. Jemec GB, Hansen U. Histology of hidradenitis suppurativa. J Am Acad Dermatol 1996; 34: 994-9.
9
Schlapbach C, Hänni T, Yawalkar N et al. Expression of the IL-23/Th17 pathway in lesions of hidradenitis suppurativa. J Am Acad Dermatol 2011; 65: 790-8.
10
van der Zee HH, de Ruiter L, van den Broecke DG et al. Elevated levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-10 in hidradenitis suppurativa skin: a rationale for targeting TNF-α and IL-1β. Br J Dermatol 2011; 164: 1292-8.
11
Zhang Q, Wang C, Liu Z et al. Notch signal suppresses Toll-like receptor-triggered inflammatory responses in macrophages by inhibiting extracellular signal-
regulated kinase 1/2-medaited nuclear factor κB activation. J Biol Chem 2012; 287: 6208-17. 12
Wolk K, Warszawska K, Hoeflich C et al. Deficiency of IL-22 contributes to a chronic inflammatory disease: pathogenetic mechanisms in acne inversa. J Immunol 2011; 186: 1228-39.
13
Alam MS, Maekawa Y, Kitamura A et al. Notch signaling drives IL-22 secretion in CD4+ T cells by stimulating the aryl hydrocarbon receptor. Proc Natl Acad Sci USA 2010; 107: 5943-8.
14
Giamarellos-Bourboulis EJ, Antonopoulou A, Petropoulou C et al. Altered innate and adaptive immune responses in patients with hidradenitis suppurativa. Br J Dermatol 2007; 156:51-6.
15
Haraguchi K, Suzuki T, Koyama N et al. Notch activation induces generation of functional NK cells from human cord blood CD34-positve cells devoid of IL-15. J Immunol 2009; 182: 6168-78.
16
Tilley AE, Harvey BG, Heguy A et al. Down-regulation of the Notch pathway in human airway epithelium in association with smoking and chronic obstructive pulmonary disease. Am J Respir Crit Car Med 2009; 179: 457-66.
17
Fain JN. Release of inflammatory mediators by human adipose tissue is enhanced in obesity and primarily by the nonfat cells: a review. Mediators Inflamm 2010; 2010: 513948.
18
Murthy A, Shao YW, Narala SR et al. Notch activation by the metalloproteinase ADAM17 regulates myeloproliferation and atopic barrier immunity by suppressing epithelial cytolkine synthesis. Immunity 2012; 36: 105-19.
19
Lapins J, Ye W, Nyrén O, Emtestam L. Incidence of cancer among patients with hidradenitis suppurativa. Arch Dermatol 2001; 137: 730-4.
20
Panelos J, Massi D. Emerging role of Notch signaling in epidermal differentiation and skin cancer. Cancer Biol Ther 2009; 8: 1986-93.
21
Church LD, Cook GP, McDermott MF. Primer: inflammasomes and interleukin 1β in inflammatory disorders. Nat Clin Pract Rheumatol 2008; 4: 34-42.
Figure Legends
Figure 1. A
Normal γ-secretase-Notch signalling. After first proteolytic cleavage of the
extracellular domain of Notch by ADAM (TACE) family metalloproteinases, second proteolytic cleavage of the Notch receptor by γ-secretase releases Notch intracellular domain (NICD), which enters the nucleus and assembles a transcriptional complex with the DNA binding protein RBP-Jκ. This complex activates the HES (Hairy and enhancer of split) and HEY (Hairy and enhancer of split-related) target genes involved in epidermal differentiation and immune regulation. B
Impaired γ-secretase-Notch signalling due to loss of function mutations of
components of the γ-secretase complex. Mutations of either the PSENEN, PSEN1 or NCSTN gene result in impaired γ-secretase activity with deficient Notch signalling.
Figure 2. Schematic model of the role of impaired Notch signalling in the pathogenesis of acne inversa. Deficient Notch signalling in AI disturbs terminal hair follicle and sebaceous gland differentiation and induces epidermal cyst formation. Impaired Notch signalling deviates immune functions of T helper cells resulting in deficient secretion of IL-22 and IL-22-mediated alterations in the synthesis of antimicrobial peptides (AMPs), insufficiently suppresses TLR-mediated IL-23 synthesis of macrophages, providing the important stimulus for the development of Th17-driven autoinflammatory immune reactions. Insufficient suppression of TLR-inflammasome (IF) interactions may further up-regulate IL-1β secretion augmenting a proinflammatory cytokine environment. Smoking, obesity and skin barrier stress by occlusion may synergistically augment autoinflammatory reactions primarily evoked by impaired Notch signalling.
