Mannan‐binding lectin exacerbates the severity of psoriasis by promoting plasmacytoid dendritic cell differentiation via the signal transducer and activator of transcription 3–interferon regulatory factor 8 axis

摘要

Abstract Psoriasis is a chronic inflammatory skin disease mediated by host immune responses. Plasmacytoid dendritic cells (pDC) and interferon (IFN)‐α secreted by pDC are involved in the initiation of psoriasis. Mannan‐binding lectin (MBL), a vital component of the complement pathway, plays a critical role in innate immune defense and the inflammatory response. Our previous study found that MBL could exacerbate skin inflammation in psoriatic mice, but the effect of MBL on pDC remains unstudied. Herein, we revealed that the circulating level of MBL was elevated in patients with psoriasis compared with the healthy controls. Moreover, the MBL level was positively correlated with disease severity, relative inflammatory cytokine levels, and peripheral blood (PB) pDC frequency in psoriasis. An in vitro study determined that the MBL protein could promote the differentiation of human pDC and upregulate the production of relative inflammatory cytokines and chemokines. Additionally, MBL‐deficient (MBL?/?) mice exhibited decreased accumulation of pDC in lymph nodes, spleens, and skin lesions with reduced secretion of pDC‐related cytokines compared with wild‐type (WT) mice in the preliminary stage of psoriasis induced by imiquimod. Notably, the differentiation of pDC from bone marrow (BM) cells derived from MBL?/? mice was weakened compared with that from WT mice upon Fms‐like tyrosine kinase 3 ligand (Flt3L) incubation. Mechanistic research indicated that the signal transducer and activator of transcription 3 (STAT3)–interferon regulatory factor 8 (IRF8) axis was responsible for MBL‐modulated pDC differentiation. In summary, these results suggest that MBL exacerbates the severity of psoriasis by enhancing pDC differentiation and pDC‐related cytokine secretion via the STAT3–IRF8 axis, thus providing a new target for psoriasis treatment.