Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, China.
Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China.
J Dermatol. 2022 May;49(5):496-507. doi: 10.1111/1346-8138.16323. Epub 2022 Mar 29.
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.
银屑病是一种由宿主免疫反应介导的慢性炎症性皮肤病。浆细胞样树突状细胞（pDC）及其分泌的干扰素（IFN）-α在银屑病的发生中起作用。甘露聚糖结合凝集素（MBL）是补体途径的重要组成部分，在固有免疫防御和炎症反应中发挥关键作用。我们之前的研究发现 MBL 可加重银屑病小鼠的皮肤炎症，但 MBL 对 pDC 的影响尚未研究。在此，我们发现与健康对照组相比，银屑病患者的循环 MBL 水平升高。此外，MBL 水平与疾病严重程度、相对炎症细胞因子水平以及银屑病患者外周血（PB）pDC 频率呈正相关。体外研究表明，MBL 蛋白可促进人 pDC 的分化，并上调相关炎症细胞因子和趋化因子的产生。此外，与野生型（WT）小鼠相比，在咪喹莫特诱导的银屑病初步阶段，MBL 缺陷（MBL）小鼠的淋巴结、脾脏和皮肤病变中 pDC 的积累减少，pDC 相关细胞因子的分泌减少。值得注意的是，与 WT 小鼠相比，MBL 小鼠骨髓（BM）细胞来源的 pDC 分化能力较弱，在 Fms 样酪氨酸激酶 3 配体（Flt3L）孵育时。机制研究表明，信号转导和转录激活因子 3（STAT3）-干扰素调节因子 8（IRF8）轴负责 MBL 调节的 pDC 分化。综上所述，这些结果表明，MBL 通过增强 pDC 分化和 pDC 相关细胞因子的分泌来加重银屑病的严重程度，通过 STAT3-IRF8 轴，为银屑病的治疗提供了一个新的靶点。
