Inhibition of SIK1 Alleviates the Pathologies of Psoriasis by Disrupting IL‐17 Signaling

Psoriasis is an inflammatory skin disease mediated by multiple immune cells, including T cells, macrophages, and dendritic cells, which exhibit complex pathologies and limited clinical treatment. Here, we found that salt‐inducible kinase 1 (SIK1) was upregulated in the imiquimod (IMQ)‐induced psoriasis mouse model. This increment may be due to a higher level of interleukin‐17, which promoted the expression of SIK1 in keratinocytes. Inhibition of SIK1 kinase activity using a small molecular inhibitor (HG‐9‐91‐01 or YKL‐06‐062) dramatically alleviated IMQ‐induced psoriasis, showing reduced epidermal thickness, inflammation, and hyperproliferative epidermal keratinocytes. Our data demonstrated that SIK1 inhibitors HG‐9‐91‐01 or YKL‐06‐062 blocked the expression of IL‐17‐induced proinflammatory cytokines and chemokines, including Il6 , Kc , and Ccl20 . Mechanistically, we found that SIK1 inhibitor HG‐9‐91‐01 or YKL‐06‐062 suppressed the phosphorylation of I κ b α and P38. Consistently, SIK1 overexpression in keratinocytes promoted the activation of I κ b α and P38. Collectively, our results reveal that SIK1 participates to promote IL17‐induced signaling through enhancing activation of NF‐ κ B and MAPKs and exacerbates psoriasis‐like skin inflammation. Thus, inhibition of SIK1 presents a potential new therapeutic target for psoriasis.