428 CD100-Plexin-B2 promotes the inflammation in psoriasis by activating NF-κB and inflammasome in keratinocytes

Abstract

Psoriasis is an inflammatory skin disease, in which keratinocytes play a crucial role in the pathogenesis. Plexin-B2 (PlxnB2) and its ligand, Semaphorin 4D (Sema4D, CD100), are originally identified as axon-guidance molecules that function during neuronal development; however, studies also showed that CD100-Plexins participate in various immune responses. To explore the function and mechanism of CD100-PlxnB2 in the pathogenesis of psoriasis. Expression and interaction of PlxnB2 and CD100 in psoriasis patients, imiquimod-induced psoriasis-like dermatitis of mice and primary keratinocytes cells were analyzed by immunohistochemistry, quantitative RT-PCR, ELISA, Western blot and co-immunoprecipitation. Inflammatory responses, cytokine expression and signaling pathway activation were analyzed by using ELISA, quantitative PCR, Western blot and flow cytometry. We found that the expression of PlxnB2 on keratinocytes was specifically increased in the lesional skin of psoriasis patients and imiquimod (IMQ)-induced psoriatic dermatitis of mice, but not atopic dermatitis patients and MC903-induced AD mouse model. The levels of soluble CD100 (sCD100) and membrane CD100 (mCD100) were elevated in the sera of psoriasis patients and on the keratinocytes of psoriatic skin, respectively. And the expression of mCD100 on T cells, monocytes and platelet, but not B cells, from PBMC of psoriasis patients was lower than that of healthy controls. By binding to PlxnB2, sCD100 promoted the production of CXCL-1, CCL-20, IL-1β and IL-18 by keratinocytes in cell culture, and activated the NLRP3 inflammasome. Moreover, CD100-PlxnB2 stimulated NF-κB signaling pathway in keratinocytes through the activation of small GTPase RhoA and Rac1. And mCD100 promoted the PlxnB2-mediated effects exerted by sCD100, and functioned as a co-receptor for PlxnB2. Our data uncovered for the first time that cooperation of CD100 and PlxnB2 promoted the inflammatory responses in keratinocytes by activating NF-κB and NLRP3 inflammasome, and participated in the pathogenesis of psoriasis. And CD100/PlxnB2 might be a potential therapeutic target for psoriasis.