CCR6 is required for IL-23–induced psoriasis-like inflammation in mice

Hedrick, Michael N.; Lonsdorf, Anke S.; Shirakawa, Aiko Konno; Lee, Chyi‐Chia Richard; Liao, Fang; Singh, Satya P.; Zhang, Hongwei H.; Grinberg, Alexander; Love, Paul E.; Hwang, Samuel T; Farber, Joshua M.

doi:10.1172/jci37378

Cited by 205 publications

(238 citation statements)

References 88 publications

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“…Intradermal injection of IL-23 is another widely used model of psoriasiform inflammation, which is robustly comparable to the Aldara model in terms of the key cellular mechanisms involved such as the induction of an IL-1R1-dependent type 17 response through direct stimulation of T cell subsets (10,33). Because TIR8 /SIGIRR has been characterized as a negative regulator of TLR7 signaling (34,35), it is possible that the enhanced dermal inflammatory phenotype observed in Tir8/Sigirr 2/2 mice in the Aldara model described above is dependent on this activity.…”

Section: Resultsmentioning

confidence: 99%

Toll IL-1R8/Single Ig IL-1–Related Receptor Regulates Psoriasiform Inflammation through Direct Inhibition of Innate IL-17A Expression by γδ T Cells

Russell

Stefańska

Kubica

et al. 2013

The Journal of Immunology

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Expression of the orphan receptor Toll IL-1R8/single Ig IL-1–related receptor has been reported to be reduced in the peripheral blood of psoriatic arthritis patients. However whether TIR8/SIGIRR activity plays a specific role in regulating psoriatic inflammation is unknown. We report that Tir8/Sigirr-deficient mice develop more severe psoriatic inflammation in both the chemical (Aldara)- and cytokine (rIL-23)-induced models of psoriasis. Increased disease severity was associated with enhanced infiltration of Vγ4+ γδ T cells that express significantly elevated levels of IL-17A. Critically, we also demonstrate that TIR8/SIGIRR activity directly suppressed innate IL-17A expression by γδ T cells in vitro and in vivo. Importantly, treatment of Tir8/Sigirr−/− mice with an IL-17A neutralization Ab reversed the enhanced disease severity observed in these mice. This study identifies TIR8/SIGIRR as a novel intrinsic negative regulator of innate IL-17A expression and characterizes a novel mechanism involved in the regulation of psoriatic inflammation.

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Section: Resultsmentioning

confidence: 99%

Toll IL-1R8/Single Ig IL-1–Related Receptor Regulates Psoriasiform Inflammation through Direct Inhibition of Innate IL-17A Expression by γδ T Cells

Russell

Stefańska

Kubica

et al. 2013

The Journal of Immunology

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“…It is known that IL-17A induces CCL20 expression in keratinocytes, a ligand for CCR6 (49)(50)(51), and directs recruitment of CCR6 + cells to psoriatic lesions. Intriguingly, IL-23-induced Ps-like inflammation required CCR6 (52). A proinflammatory subset of γδ T cells (Vγ9Vδ2) producing IL-17A was recently reported to home the skin compartments and activate keratinocytes in patients with Ps (53).…”

Section: Discussionmentioning

confidence: 99%

Mannan induces ROS-regulated, IL-17A–dependent psoriasis arthritis-like disease in mice

Khmaladze

Kelkka

Guérard

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

119

148

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Significance We identified a previously undescribed disease mechanism for psoriasis (Ps) and psoriasis arthritis (PsA)-like disease by developing a new mouse model having characteristic features similar to those of Ps and PsA in human patients. Mannan-induced activation of tissue macrophages triggers IL-17A secretion from γδ T cells, causing Ps-like inflammation. Such inflammation was significantly increased under a reduced oxidative environment. Increased frequency of monocytes/macrophages, depletion experiments, and the disease suppressor function of macrophage-derived reactive oxygen species clearly argue in favor of a role for monocytes/macrophages in this disease model, which is in accordance with the findings in patients with the psoriatic form of skin lesions and arthritis. This novel PsA model could be immensely useful to test new therapeutics for patients with Ps and PsA.

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“…Psoriasis-like inflammation induced upon intradermal injections of IL-23 in mice was reported to be largely dependent on the presence of IL-17RA; however other studies have highlighted the critical contributions of IL-22 (27)(28)(29). Topical application of the TLR7/8 ligand imiquimod (IMQ) induces skin inflammation in mice that mimics various aspects of human psoriasis (5,30).…”

Section: Significancementioning

confidence: 99%

IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms

Wang

Pisitkun

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

128

114

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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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CCR6 is required for IL-23–induced psoriasis-like inflammation in mice

Cited by 205 publications

References 88 publications

Toll IL-1R8/Single Ig IL-1–Related Receptor Regulates Psoriasiform Inflammation through Direct Inhibition of Innate IL-17A Expression by γδ T Cells

Toll IL-1R8/Single Ig IL-1–Related Receptor Regulates Psoriasiform Inflammation through Direct Inhibition of Innate IL-17A Expression by γδ T Cells

Mannan induces ROS-regulated, IL-17A–dependent psoriasis arthritis-like disease in mice

IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms

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