Gain-of-Function Mutation of Card14 Leads to Spontaneous Psoriasis-like Skin Inflammation through Enhanced Keratinocyte Response to IL-17A

Publication date: Available online 3 July 2018

Source: Immunity

Author(s): Mingchao Wang, Shanshan Zhang, Guoxing Zheng, Junjiu Huang, Zhou Songyang, Xueqiang Zhao, Xin Lin

Summary

Genetic mutations of CARD14 (encoding CARMA2) are observed in psoriasis patients. Here we showed that Card14^E138A/+ and Card14^ΔQ136/+ mice developed spontaneous psoriasis-like skin inflammation, which resulted from constitutively activated CARMA2 via self-aggregation leading to the enhanced activation of the IL-23-IL-17A cytokine axis. Card14^−/− mice displayed attenuated skin inflammation in the imiquimod-induced psoriasis model due to impaired IL-17A signaling in keratinocytes. CARMA2, mainly expressed in keratinocytes, associates with the ACT1-TRAF6 signaling complex and mediates IL-17A-induced NF-κB and MAPK signaling pathway activation, which leads to expression of pro-inflammatory factors. Thus, CARMA2 serves as a key mediator of IL-17A signaling and its constitutive activation in keratinocytes leads to the onset of psoriasis, which indicates an important role of NF-κB activation in keratinocytes in psoriatic initiation.

Graphical Abstract

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