Abstract
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 Iκbα and P38. Consistently, SIK1 overexpression in keratinocytes promoted the activation of Iκbα and P38. Collectively, our results reveal that SIK1 participates to promote IL17-induced signaling through enhancing activation of NF-κB and MAPKs and exacerbates psoriasis-like skin inflammation. Thus, inhibition of SIK1 presents a potential new therapeutic target for psoriasis.