Abstract：
BACKGROUND: Meteorin-like protein (METRNL)/Interleukin-41 (IL-41) is a novel immune-secreted cytokine/myokine involved in several inflammatory diseases. However, how METRNL exerts its regulatory properties on skin inflammation remains elusive. This study aims to elucidate the functionality and regulatory mechanism of METRNL in atopic dermatitis (AD).
METHODS: METRNL levels were determined in skin and serum samples from patients with AD and subsequently verified in the vitamin D3 analogue MC903-induced AD-like mice model. The cellular target of METRNL activity was identified by multiplex immunostaining, single-cell RNA-seq and RNA-seq.
RESULTS: METRNL was significantly upregulated in lesions and serum of patients with dermatitis compared to healthy controls (p <.05). Following repeated MC903 exposure, AD model mice displayed elevated levels of METRNL in both ears and serum. Administration of recombinant murine METRNL protein (rmMETRNL) ameliorated allergic skin inflammation and hallmarks of AD in mice, whereas blocking of METRNL signaling led to the opposite. METRNL enhanced β-Catenin activation, limited the expression of Th2-related molecules that attract the accumulation of Arginase-1 (Arg1)hi macrophages, dendritic cells, and activated mast cells.
CONCLUSIONS: METRNL can bind to KIT receptor and subsequently alleviate the allergic inflammation of AD by inhibiting the expansion of immune cells, and downregulating inflammatory gene expression by regulating the level of active WNT pathway molecule β-Catenin.
METHODS: METRNL levels were determined in skin and serum samples from patients with AD and subsequently verified in the vitamin D3 analogue MC903-induced AD-like mice model. The cellular target of METRNL activity was identified by multiplex immunostaining, single-cell RNA-seq and RNA-seq.
RESULTS: METRNL was significantly upregulated in lesions and serum of patients with dermatitis compared to healthy controls (p <.05). Following repeated MC903 exposure, AD model mice displayed elevated levels of METRNL in both ears and serum. Administration of recombinant murine METRNL protein (rmMETRNL) ameliorated allergic skin inflammation and hallmarks of AD in mice, whereas blocking of METRNL signaling led to the opposite. METRNL enhanced β-Catenin activation, limited the expression of Th2-related molecules that attract the accumulation of Arginase-1 (Arg1)hi macrophages, dendritic cells, and activated mast cells.
CONCLUSIONS: METRNL can bind to KIT receptor and subsequently alleviate the allergic inflammation of AD by inhibiting the expansion of immune cells, and downregulating inflammatory gene expression by regulating the level of active WNT pathway molecule β-Catenin.
摘要：
背景：Meteorin-likeprotein(METRNL)/Interleukin-41(IL-41)是一种新型的免疫分泌的细胞因子/肌动蛋白，参与多种炎性疾病。然而,METRNL如何发挥其对皮肤炎症的调节特性仍然难以捉摸。本研究旨在阐明METRNL在特应性皮炎（AD）中的功能和调节机制。
方法：在AD患者的皮肤和血清样品中测定METRNL水平，随后在维生素D3类似物MC903诱导的AD样小鼠模型中进行验证。通过多重免疫染色鉴定METRNL活性的细胞靶标，单细胞RNA-seq和RNA-seq。
结果：与健康对照组相比，皮炎患者的皮损和血清中的METRNL显著上调（p<0.05）。重复MC903曝光后，AD模型小鼠在耳朵和血清中显示出升高的METRNL水平。施用重组鼠METRNL蛋白(rmMETRNL)改善小鼠过敏性皮肤炎症和AD的标志,而METRNL信号传导的阻断则相反。METRNL增强β-连环蛋白激活，限制了吸引精氨酸酶-1（Arg1）在巨噬细胞中积累的Th2相关分子的表达，树突状细胞,和激活的肥大细胞。
结论：METRNL可与KIT受体结合，通过抑制免疫细胞的扩增来减轻AD的过敏性炎症，并通过调节WNT途径活性分子β-Catenin的水平下调炎症基因的表达。
方法：在AD患者的皮肤和血清样品中测定METRNL水平，随后在维生素D3类似物MC903诱导的AD样小鼠模型中进行验证。通过多重免疫染色鉴定METRNL活性的细胞靶标，单细胞RNA-seq和RNA-seq。
结果：与健康对照组相比，皮炎患者的皮损和血清中的METRNL显著上调（p<0.05）。重复MC903曝光后，AD模型小鼠在耳朵和血清中显示出升高的METRNL水平。施用重组鼠METRNL蛋白(rmMETRNL)改善小鼠过敏性皮肤炎症和AD的标志,而METRNL信号传导的阻断则相反。METRNL增强β-连环蛋白激活，限制了吸引精氨酸酶-1（Arg1）在巨噬细胞中积累的Th2相关分子的表达，树突状细胞,和激活的肥大细胞。
结论：METRNL可与KIT受体结合，通过抑制免疫细胞的扩增来减轻AD的过敏性炎症，并通过调节WNT途径活性分子β-Catenin的水平下调炎症基因的表达。
