TREM2 Deficiency Regulates Macrophage Apoptosis and Repair in Radiation-Induced Skin Injury

Radiation-induced skin injury (RISI) is a common and debilitating complication of radiotherapy, characterized by persistent inflammation and delayed wound healing. Macrophages play a central role in this process; however, the molecular mechanisms governing their dysfunction under radiation stress remain poorly understood. To elucidate the role of triggering receptor expressed on myeloid cells 2 (TREM2) in macrophage regulation after irradiation, we combined single-cell RNA sequencing, in vivo mouse models, and in vitro macrophage assays. Conditional knockout mice ( LysM Cre Trem2 flox/flox ) were used to selectively delete Trem2 in macrophages. Radiation induced a distinct TREM2 + macrophage subset; however, despite elevated Trem2 mRNA, protein levels declined due to ADAM17-mediated shedding driven by radiation-induced reactive oxygen species (ROS) accumulation and NRF2 activation. Inhibition or small interfering RNA (siRNA)-mediated knockdown of ADAM17 restored TREM2 protein expression, reduced soluble TREM2 release, improved macrophage survival, and promoted anti-inflammatory M2 polarization. Conversely, Trem2 deficiency enhanced apoptosis, sustained inflammation, and delayed wound healing, whereas Trem2 overexpression or local adoptive transfer of TREM2 + macrophages accelerated tissue repair. Mechanistically, TREM2 conferred radioprotection through extracellular signal-regulated kinase (ERK) pathway activation, linking the ROS–NRF2–ADAM17 axis to TREM2–ERK signaling in macrophage survival and polarization. Collectively, these findings identify a novel regulatory cascade, ROS–NRF2–ADAM17–TREM2–ERK, that governs macrophage fate under irradiation. Targeting this pathway or supplementing TREM2 + macrophages may offer promising therapeutic strategies for mitigating RISI.