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Shane E Russell, Anna M Stefanska, Malgorzata Kubica, Rachel M Horan, Alberto Mantovani, Cecilia Garlanda, Padraic G Fallon, Patrick T Walsh, Toll IL-1R8/Single Ig IL-1–Related Receptor Regulates Psoriasiform Inflammation through Direct Inhibition of Innate IL-17A Expression by γδ T Cells, The Journal of Immunology, Volume 191, Issue 6, September 2013, Pages 3337–3346, https://doi.org/10.4049/jimmunol.1300828
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Abstract
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.