Trem2 acts as a non‐classical receptor of interleukin‐4 to promote diabetic wound healing

作者：Xinlin Zhu, Chao Zhang, Weiwei Jiang, Zhaoxiang Zeng, Keming Zhang, Mingwei Du, Juan Chen, Qian Wu, Wanqing Liao, Youming Chen, Wenjie Fang, Weihua Pan · 发表于：Clinical and Translational Medicine · 年份：2024 · DOI：10.1002/ctm2.70026 · 被引用次数：15 · 研究领域：Inflammation biomarkers and pathways、Immune cells in cancer、Neuroinflammation and Neurodegeneration Mechanisms

BACKGROUND: The immunoglobulin superfamily protein Trem2 (triggering receptor expressed on myeloid cells 2) is primarily expressed on myeloid cells where it functions to regulate macrophage-related immune response induction. While macrophages are essential mediators of diabetic wound healing, the specific regulatory role that Trem2 plays in this setting remains to be established. OBJECTIVE: This study was developed to explore the potential importance of Trem2 signalling in diabetic wound healing and to clarify the underlying mechanisms through which it functions. METHODS AND RESULTS: Following wound induction, diabetic model mice exhibited pronounced upregulation of Trem2 expression, which was primarily evident in macrophages. No cutaneous defects were evident in mice bearing a macrophage-specific knockout of Trem2 (T2-cKO), but they induced more pronounced inflammatory responses and failed to effectively repair cutaneous wounds, with lower levels of neovascularization, slower rates of wound closure, decreased collagen deposition following wounding. Mechanistically, we showed that interleukin (IL)-4 binds directly to Trem2, inactivating MAPK/AP-1 signalling to suppress the expression of inflammatory and chemoattractant factors. Co-culture of fibroblasts and macrophages showed that macrophages from T2-cKO mice suppressed the in vitro activation and proliferation of dermal fibroblasts through upregulation of leukaemia inhibitory factor (Lif). Injecting soluble Trem2 in vivo was...