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In this article, we show that neither genetic ablation of Il17a nor elimination of T cells was sufficient to restrain the skin inflammation in a CARD14-E138A-mutation-induced psoriasis-like mouse model, whereas depletion of Il23, which extremely blocked the IL-23\/T17 axis, was more effective. Targeting CBM complex by conditional deletion of MALT1 or BCL10 in keratinocytes abrogated both the cutaneous and systemic inflammation of heterozygous Card14E138A\/+ mice. Selective inactivation of keratinocyte-specific MALT1 proteolytic activity strongly ameliorated the Card14E138A\/+- and Card14\u0394Q136\/+-induced skin disease, which was reproduced by using the imiquimod-induced mouse model. Together, our results suggest a sequence of events under CARD14-mutation-induced psoriasis condition that keratinocyte-intrinsic activation of CBM complex initiates the skin inflammation depending on the IL-23\/T17 axis. Targeting keratinocytes by inactivation of MALT1 paracaspase activity might be a promising therapeutic target for early psoriasis treatment.<\/jats:p>","DOI":"10.4049\/jimmunol.2001031","type":"journal-article","created":{"date-parts":[[2021,1,8]],"date-time":"2021-01-08T20:31:39Z","timestamp":1610137899000},"page":"839-848","source":"Crossref","is-referenced-by-count":17,"title":["Intrinsic Abnormalities of Keratinocytes Initiate Skin Inflammation through the IL-23\/T17 Axis in a MALT1-Dependent Manner"],"prefix":"10.1093","volume":"206","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4174-3372","authenticated-orcid":false,"given":"Shanshan","family":"Zhang","sequence":"first","affiliation":[{"name":"Institute for Immunology, Tsinghua University School of Medicine , Beijing 100084 ,","place":["China"]},{"name":"Department of Basic Medical Sciences, Tsinghua University School of Medicine , Beijing 100084 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