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

BackgroundThe 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.ObjectiveThis 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 resultsFollowing 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 also sufficient to significantly curtail inflammatory responses and to promote diabetic wound healing.ConclusionsThese analyses offer novel insight into the role of IL-4/Trem2 signalling as a mediator of myeloid cell-fibroblast crosstalk that may represent a viable therapeutic target for efforts to enhance diabetic wound healing. This study elucidates the pivotal role of TREM2 in diabetic wound healing. This study identified the key regulatory gene involved in diabetic wound healing as TREM2. This study has found that IL-4 functions as an upstream ligand, activating TREM2. This study provides Evidence of the regulatory effects of macrophages by IL-4/TREM2/AP-1/LIF pathway on fibroblasts. This study validated the therapeutic potential using the sTREM2. image