Precision Research Center for Refractory Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China.
State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
Nat Commun. 2023 Apr 10;14(1):2004. doi: 10.1038/s41467-023-37798-x.
Dermal fibroblasts and cutaneous nerves are important players in skin diseases, while their reciprocal roles during skin inflammation have not been characterized. Here we identify an inflammation-induced subset of papillary fibroblasts that promotes aberrant neurite outgrowth and psoriasiform skin inflammation by secreting the extracellular matrix protein tenascin-C (TNC). Single-cell analysis of fibroblast lineages reveals a Tnc papillary fibroblast subset with pro-axonogenesis and neuro-regulation transcriptomic hallmarks. TNC overexpression in fibroblasts boosts neurite outgrowth in co-cultured neurons, while fibroblast-specific TNC ablation suppresses hyperinnervation and alleviates skin inflammation in male mice modeling psoriasis. Dermal γδT cells, the main producers of type 17 pathogenic cytokines, frequently contact nerve fibers in mouse psoriasiform lesions and are likely modulated by postsynaptic signals. Overall, our results highlight the role of an inflammation-responsive fibroblast subset in facilitating neuro-immune synapse formation and suggest potential avenues for future therapeutic research.
皮肤成纤维细胞和皮肤神经是皮肤疾病的重要参与者，但其在皮肤炎症中的相互作用尚未得到描述。在这里，我们鉴定出一种炎症诱导的乳头成纤维细胞亚群，通过分泌细胞外基质蛋白 tenascin-C（TNC）促进异常轴突生长和银屑病样皮肤炎症。成纤维细胞谱系的单细胞分析揭示了具有促轴突发生和神经调节转录组特征的 Tnc 乳头成纤维细胞亚群。成纤维细胞中 TNC 的过表达可增强共培养神经元中的神经突生长，而纤维母细胞特异性 TNC 消融可抑制过度神经支配并减轻模拟银屑病的雄性小鼠的皮肤炎症。皮肤 γδT 细胞是 17 型致病细胞因子的主要产生者，在小鼠银屑病样病变中经常与神经纤维接触，并且可能受到突触后信号的调节。总的来说，我们的研究结果强调了一种炎症反应性成纤维细胞亚群在促进神经免疫突触形成中的作用，并为未来的治疗研究提供了潜在的途径。
