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
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.

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Teaser

Mutations in the CARMA2 gene (CARD14) are identified in psoriasis patients, but whether and how these mutations initiate psoriasis is unclear. Wang et al. reveal that Card14^E138A/+ mice develop spontaneous psoriasis via CARMA2 self-aggregation and activation, and the deficiency or mutation of Card14 affects the activation of IL-17A signaling in keratinocytes.


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