IL-17 Drives Psoriatic Inflammation Via Distinct, Target Cell-specific Mechanisms

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2014 Aug 6

PMID 25092341

Citations 75

Authors

Hye-Lin Ha

Hongshan Wang

Prapaporn Pisitkun

Jin-Chul Kim

Ilaria Tassi

Wanhu Tang

Maria I Morasso

Mark C Udey

Ulrich Siebenlist

Affiliations

Soon will be listed here.

Abstract

Psoriasis is a chronic inflammatory skin disease characterized by abnormal keratinocyte proliferation and differentiation and by an influx of inflammatory cells. The mechanisms underlying psoriasis in humans and in mouse models are poorly understood, although evidence strongly points to crucial contributions of IL-17 cytokines, which signal via the obligatory adaptor CIKS/Act1. Here we identify critical roles of CIKS/Act1-mediated signaling in imiquimod-induced psoriatic inflammation, a mouse model that shares features with the human disease. We found that IL-17 cytokines/CIKS-mediated signaling into keratinocytes is essential for neutrophilic microabscess formation and contributes to hyperproliferation and markedly attenuated differentiation of keratinocytes, at least in part via direct effects. In contrast, IL-17 cytokines/CIKS-mediated signaling into nonkeratinocytes, particularly into dermal fibroblasts, promotes cellular infiltration and, importantly, leads to enhanced the accumulation of IL-17-producing γδT cells in skin, comprising a positive feed-forward mechanism. Thus, CIKS-mediated signaling is central in the development of both dermal and epidermal hallmarks of psoriasis, inducing distinct pathologies via target cell-specific effects. CIKS-mediated signaling represents a potential therapeutic target in psoriasis.

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References

Papp K, Leonardi C, Menter A, Ortonne J, Krueger J, Kricorian G . Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med. 2012; 366(13):1181-9. DOI: 10.1056/NEJMoa1109017. View

El Malki K, Karbach S, Huppert J, Zayoud M, Reissig S, Schuler R . An alternative pathway of imiquimod-induced psoriasis-like skin inflammation in the absence of interleukin-17 receptor a signaling. J Invest Dermatol. 2012; 133(2):441-51. DOI: 10.1038/jid.2012.318. View

Cai Y, Shen X, Ding C, Qi C, Li K, Li X . Pivotal role of dermal IL-17-producing γδ T cells in skin inflammation. Immunity. 2011; 35(4):596-610. PMC: 3205267. DOI: 10.1016/j.immuni.2011.08.001. View

Harper E, Guo C, Rizzo H, Lillis J, Kurtz S, Skorcheva I . Th17 cytokines stimulate CCL20 expression in keratinocytes in vitro and in vivo: implications for psoriasis pathogenesis. J Invest Dermatol. 2009; 129(9):2175-83. PMC: 2892172. DOI: 10.1038/jid.2009.65. View

Hirota K, Ahlfors H, Duarte J, Stockinger B . Regulation and function of innate and adaptive interleukin-17-producing cells. EMBO Rep. 2011; 13(2):113-20. PMC: 3271338. DOI: 10.1038/embor.2011.248. View

Sonder S, Saret S, Tang W, Sturdevant D, Porcella S, Siebenlist U . IL-17-induced NF-kappaB activation via CIKS/Act1: physiologic significance and signaling mechanisms. J Biol Chem. 2011; 286(15):12881-90. PMC: 3075635. DOI: 10.1074/jbc.M110.199547. View

van der Fits L, Mourits S, Voerman J, Kant M, Boon L, Laman J . Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J Immunol. 2009; 182(9):5836-45. DOI: 10.4049/jimmunol.0802999. View

Benoit S, Toksoy A, Ahlmann M, Schmidt M, Sunderkotter C, Foell D . Elevated serum levels of calcium-binding S100 proteins A8 and A9 reflect disease activity and abnormal differentiation of keratinocytes in psoriasis. Br J Dermatol. 2006; 155(1):62-6. DOI: 10.1111/j.1365-2133.2006.07198.x. View

Qian Y, Liu C, Hartupee J, Altuntas C, Gulen M, Jane-Wit D . The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nat Immunol. 2007; 8(3):247-56. DOI: 10.1038/ni1439. View

10.

Papp K, Reid C, Foley P, Sinclair R, Salinger D, Williams G . Anti-IL-17 receptor antibody AMG 827 leads to rapid clinical response in subjects with moderate to severe psoriasis: results from a phase I, randomized, placebo-controlled trial. J Invest Dermatol. 2012; 132(10):2466-2469. DOI: 10.1038/jid.2012.163. View

11.

Chan J, Blumenschein W, Murphy E, Diveu C, Wiekowski M, Abbondanzo S . IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis. J Exp Med. 2006; 203(12):2577-87. PMC: 2118145. DOI: 10.1084/jem.20060244. View

12.

Onishi R, Park S, Hanel W, Ho A, Maitra A, Gaffen S . SEF/IL-17R (SEFIR) is not enough: an extended SEFIR domain is required for il-17RA-mediated signal transduction. J Biol Chem. 2010; 285(43):32751-32759. PMC: 2963341. DOI: 10.1074/jbc.M110.121418. View

13.

Nomura I, Gao B, Boguniewicz M, Darst M, Travers J, Leung D . Distinct patterns of gene expression in the skin lesions of atopic dermatitis and psoriasis: a gene microarray analysis. J Allergy Clin Immunol. 2003; 112(6):1195-202. DOI: 10.1016/j.jaci.2003.08.049. View

14.

Claudio E, Sonder S, Saret S, Carvalho G, Ramalingam T, Wynn T . The adaptor protein CIKS/Act1 is essential for IL-25-mediated allergic airway inflammation. J Immunol. 2009; 182(3):1617-30. PMC: 2630122. DOI: 10.4049/jimmunol.182.3.1617. View

15.

Huffmeier U, Uebe S, Ekici A, Bowes J, Giardina E, Korendowych E . Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis. Nat Genet. 2010; 42(11):996-9. PMC: 2981079. DOI: 10.1038/ng.688. View

16.

Di Cesare A, Di Meglio P, Nestle F . The IL-23/Th17 axis in the immunopathogenesis of psoriasis. J Invest Dermatol. 2009; 129(6):1339-50. DOI: 10.1038/jid.2009.59. View

17.

Toichi E, Tachibana T, Furukawa F . Rapid improvement of psoriasis vulgaris during drug-induced agranulocytosis. J Am Acad Dermatol. 2000; 43(2 Pt 2):391-5. DOI: 10.1067/mjd.2000.103264. View

18.

Hennings H, Michael D, Cheng C, Steinert P, Holbrook K, Yuspa S . Calcium regulation of growth and differentiation of mouse epidermal cells in culture. Cell. 1980; 19(1):245-54. DOI: 10.1016/0092-8674(80)90406-7. View

19.

Gray E, Suzuki K, Cyster J . Cutting edge: Identification of a motile IL-17-producing gammadelta T cell population in the dermis. J Immunol. 2011; 186(11):6091-5. PMC: 3098921. DOI: 10.4049/jimmunol.1100427. View

20.

Sutton C, Lalor S, Sweeney C, Brereton C, Lavelle E, Mills K . Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity. 2009; 31(2):331-41. DOI: 10.1016/j.immuni.2009.08.001. View