Proinflammatory effect of HMGB1 on keratinocytes: an autocrine mechanism underlying psoriasis development

Abstract

Psoriasis is an autoimmune skin disease, in which keratinocytes play a crucial pathogenic role. High-mobility group protein B1 (HMGB1) is an inflammatory factor that can be released from keratinocyte nuclei in psoriatic lesions. We aimed to investigate the proinflammatory effect of HMGB1 on keratinocytes and the contribution of HMGB1 to psoriasis development. Normal human keratinocytes were treated with recombinant human HMGB1, and the production of inflammatory factors and the intermediary signaling pathways were examined. Furthermore, the imiquimod-induced psoriasis-like mouse model was used to investigate the role of HMGB1 in psoriasis development in vivo. A total of eleven inflammatory factors were identified to be up-regulated by HMGB1 in keratinocytes, among which interleukin-18 (IL-18) showed the greatest change. We then found that the activation of the NF-κB signaling pathway and inflammasomes accounted for HMGB1-induced IL-18 expression and secretion. Moreover, HMGB1 and downstream IL-18 contributed to the formation of psoriasiform dermatitis in the imiquimod-treated mice. In addition, T helper 17 immune response in the psoriasis-like mouse model could be inhibited by both HMGB1 and IL-18 blockade. Our findings indicate that secreted HMGB1 from keratinocytes can facilitate the production and secretion of inflammatory factors like IL-18 in keratinocytes in an autocrine way, thus promoting the development of psoriasis. Blocking the proinflammatory function of the HMGB1/IL-18 axis may be useful for psoriasis treatment in the future.

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