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

• Published in: Immunity (Cambridge, Mass.) Mass.), 2018-07, Vol.49 (1), p.66-79.e5
• Main Authors: Wang, Mingchao, Zhang, Shanshan, Zheng, Guoxing, Huang, Junjiu, Songyang, Zhou, Zhao, Xueqiang, Lin, Xin
• Format: Article
• Language: English
• Subjects: Activation; Adaptor Proteins, Signal Transducing - metabolism; Animals; CARD Signaling Adaptor Proteins - chemistry; CARD Signaling Adaptor Proteins - deficiency; CARD Signaling Adaptor Proteins - genetics; CARD Signaling Adaptor Proteins - metabolism; Cell Line; Cytokines; Cytokines - genetics; Cytokines - metabolism; Dermatitis - genetics; Dermatitis - physiopathology; Gain of Function Mutation; Gene Expression Regulation - drug effects; Genotype & phenotype; Guanylate Kinases - chemistry; Guanylate Kinases - deficiency; Guanylate Kinases - genetics; Guanylate Kinases - metabolism; HEK293 Cells; Humans; Imiquimod; Immunoglobulins; Inflammation; Interleukin 23; Interleukin-17 - metabolism; Keratinocytes; Keratinocytes - metabolism; Keratinocytes - pathology; MAP kinase; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; NF-κB protein; Pathogenesis; Proteins; Psoriasis; Psoriasis - chemically induced; Psoriasis - genetics; Psoriasis - physiopathology; Signal Transduction; Signaling; Skin; Statistical analysis; T-Lymphocyte Subsets - metabolism; TNF Receptor-Associated Factor 6 - metabolism; TRAF6 protein
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2018.05.012

Genetic mutations of CARD14 (encoding CARMA2) are observed in psoriasis patients. Here we showed that Card14E138A/+ and Card14ΔQ136/+ 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. [Display omitted] •Card14E138A/+ and Card14ΔQ136/+ mice develop spontaneous psoriasis-like phenotype•αβ T cells, not γδ T cells, are the main source of IL-17A in Card14E138A/+ mice•Card14 E138A mutation leads to CARMA2 aggregation and activation•CARMA2 mediates IL-17A signaling by interacting with the ACT1-TRAF6 complex 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 Card14E138A/+ 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.