State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China.
Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China.
Cell Death Dis. 2024 Aug 17;15(8):598. doi: 10.1038/s41419-024-06994-y.
The mechanisms underlying tissue repair in response to damage have been one of main subjects of investigation. Here we leverage the wound-induced hair neogenesis (WIHN) models in adult mice to explore the correlation between degree of damage and the healing process and outcome. The multimodal analysis, in combination with single-cell RNA sequencing help to explore the difference in wounds of gentle and heavy damage degrees, identifying the potential role of toll-like receptor 9 (TLR9) in sensing the injury and regulating the immune reaction by promoting the migration of γδT cells. The TLR9 deficient mice or wounds injected with TLR9 antagonist have greatly impaired healing and lower WIHN levels. Inhibiting the migration of γδT cells or knockout of γδT cells also suppress the wound healing and regeneration, which can't be rescued by TLR9agonist. Finally, the amphiregulin (AREG) is shown as one of most important effectors secreted by γδT cells and keratinocytes both in silicon or in the laboratory, whose expression influences WIHN levels and the expression of stem cell markers. In total, our findings reveal a previously unrecognized role for TLR9 in sensing skin injury and influencing the tissue repair and regeneration by modulation of the migration of γδT cells, and identify the TLR9-γδT cells-areg axis as new potential targets for enhancing tissue regeneration.
组织在损伤后的修复机制一直是研究的主要课题之一。在这里，我们利用成年小鼠的诱导性毛发新生（WIHN）模型来探索损伤程度与修复过程和结果之间的相关性。多模态分析结合单细胞 RNA 测序有助于探索轻度和重度损伤的伤口之间的差异，确定 Toll 样受体 9（TLR9）在感知损伤和通过促进 γδT 细胞迁移来调节免疫反应中的潜在作用。TLR9 缺陷小鼠或用 TLR9 拮抗剂注射的伤口愈合严重受损，WIHN 水平降低。抑制 γδT 细胞的迁移或敲除 γδT 细胞也会抑制伤口愈合和再生，而 TLR9 激动剂不能挽救这种情况。最后， amphiregulin（AREG）被证明是 γδT 细胞和角质形成细胞在硅或实验室中分泌的最重要的效应物之一，其表达影响 WIHN 水平和干细胞标志物的表达。总的来说，我们的研究结果揭示了 TLR9 在感知皮肤损伤和通过调节 γδT 细胞迁移影响组织修复和再生中的先前未被认识的作用，并确定了 TLR9-γδT 细胞-AREG 轴作为增强组织再生的新的潜在靶点。
