Sensory neuron-derived TAFA4 promotes macrophage tissue repair functions
Sensory neuron-derived TAFA4 promotes macrophage tissue repair functions
复制标题
感觉神经元源性TAFA4促进巨噬细胞组织修复功能
DOI：
10.1038/s41586-021-03563-7
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发表时间：
2021-05-19
期刊：
影响因子：
64.8
通讯作者：
Ugolini, Sophie
中科院分区：
文献类型：
--
作者：
Hoeffel, Guillaume;Debroas, Guilhaume;Ugolini, Sophie
炎症是对组织损伤的一种防御反应，需要严格的监管，以防止受损的愈合。组织驻留的巨噬细胞在组织修复中起着关键作用(1)，但在愈合过程中调节炎症和促修复巨噬细胞反应之间平衡的确切分子机制仍然知之甚少。在这里，我们展示了感觉神经元在促进巨噬细胞的组织修复功能中的主要作用。在类似晒伤的小鼠皮肤损伤模型中，有条件地消融表达Gα(I)相互作用蛋白(GINIP)的感觉神经元会导致组织再生缺陷和真皮纤维化。对潜在分子机制的阐明揭示了神经肽TAFA4的关键作用，它是由C低阈值机械感受器在皮肤中产生的-GINIP(+)神经元的一个子集。TAFA4在体外直接调节巨噬细胞的炎症状态。对Tafa4基因缺陷小鼠的体内研究表明，TAFA4促进紫外线诱导皮肤损伤后真皮巨噬细胞产生IL-10。这个TAFA4-IL-10轴还确保IL-10(+)TIM4(+)真皮巨噬细胞的存活和维持，减少皮肤炎症，促进组织再生。这些结果揭示了神经肽TAFA4驱动的神经免疫调节途径，促进巨噬细胞的抗炎功能，防止组织损伤后的纤维化，并可能为炎症性疾病的治疗开辟新的前景。
Inflammation is a defence response to tissue damage that requires tight regulation in order to prevent impaired healing. Tissue-resident macrophages have a key role in tissue repair(1), but the precise molecular mechanisms that regulate the balance between inflammatory and pro-repair macrophage responses during healing remain poorly understood. Here we demonstrate a major role for sensory neurons in promoting the tissue-repair function of macrophages. In a sunburn-like model of skin damage in mice, the conditional ablation of sensory neurons expressing the G alpha(i)-interacting protein (GINIP) results in defective tissue regeneration and in dermal fibrosis. Elucidation of the underlying molecular mechanisms revealed a crucial role for the neuropeptide TAFA4, which is produced in the skin by C-low threshold mechanoreceptors-a subset of GINIP(+) neurons. TAFA4 modulates the inflammatory profile of macrophages directly in vitro. In vivo studies in Tafa4-deficient mice revealed that TAFA4 promotes the production of IL-10 by dermal macrophages after UV-induced skin damage. This TAFA4-IL-10 axis also ensures the survival and maintenance of IL-10(+)TIM4(+) dermal macrophages, reducing skin inflammation and promoting tissue regeneration. These results reveal a neuroimmune regulatory pathway driven by the neuropeptide TAFA4 that promotes the anti-inflammatory functions of macrophages and prevents fibrosis after tissue damage, and could lead to new therapeutic perspectives for inflammatory diseases.