Abstract
Ischemia-reperfusion injury (IRI) severely impairs the function of native and transplanted kidneys, with Arg1(+) macrophages playing a pivotal role in tubular regeneration. The triggering receptor expressed on myeloid cells 2 (Trem2) mediates debris clearance by recognizing lipids from injured cells, but its role in Arg1(+) macrophage survival remains unclear. Here, we show that Trem2 not only regulates the phagocytic activity of Arg1(+) macrophages but also sustains their survival. Single-cell transcriptomics revealed marked Trem2 upregulation in macrophages after IRI, predominantly in the Arg1(hi)Ecm1(hi) ECM-Remodeling Mac subset. Trajectory analysis indicated coordinated Trem2 and Arg1 expression during macrophage differentiation, while intercellular signaling analysis showed that IRI enhanced Apoe-Trem2-mediated communication among Arg1(hi)Ecm1(hi) ECM-Remodeling Mac, promoting debris clearance. In vivo, Trem2(+)Arg1(+)F4/80(+) macrophages abundantly infiltrated the kidney early after IRI, whereas inhibition of Trem2 aggravated kidney injury and further impaired kidney function. In vitro, tubular debris induced Trem2 expression and proliferation in Arg1(+) macrophages, whereas Trem2 knockdown or pharmacological inhibition of Trem2 reduced proliferation, increased apoptosis, and impaired their ability to support tubular epithelial repair via paracrine polyamines, EGF, and VEGF. Transcriptomic analysis further showed that Trem2 knockdown upregulated Pten and suppressed the anti-apoptotic protein Bcl2 in Arg1(+) macrophages, thereby reducing cell viability, while a Pten inhibitor VO-Ohpic reversed these effects. Together, these findings identify a previously unrecognized mechanism by which tubular debris sustains Arg1(+) macrophage survival via Trem2 activation and support targeting Trem2 and downstream PI3K-AKT signaling to enhance macrophage-mediated kidney repair.