Article Highlight | 17-Mar-2026

TREM2 safeguards macrophage survival and promotes repair in radiation-induced skin injury

Research

Figure 1:Radiation-induced ROS–NRF2–ADAM17–mediated TREM2 shedding results in TREM2 deficiency, thereby impairing macrophage polarization and radioresistance.

image: 

Figure 1:Radiation-induced ROS–NRF2–ADAM17–mediated TREM2 shedding results in TREM2 deficiency, thereby impairing macrophage polarization and radioresistance.

view more 

Credit: Copyright © 2025 Zijian Chen et al.

Background

Radiation-induced skin injury (RISI) is a common and debilitating complication of radiotherapy, affecting up to 95% of cancer patients receiving radiation treatment. Persistent inflammation and delayed wound healing remain major clinical challenges, with limited effective therapeutic options.

Macrophages play a central role in coordinating inflammatory responses and tissue repair. However, how macrophage fate is regulated under radiation stress remains poorly understood.

Key Findings

Using single-cell RNA sequencing, mouse models, and in vitro macrophage assays, the researchers identify TREM2 as a critical regulator of macrophage survival and repair in RISI.

Radiation induces a distinct TREM2⁺ macrophage subset that acts as a central hub in inflammatory signaling networks. While Trem2 transcription is upregulated after irradiation, TREM2 protein levels decline due to radiation-induced oxidative stress.Mechanistically, radiation activates the ROS–NRF2–ADAM17 axis, promoting TREM2 shedding and release of soluble TREM2(Figure1).

TREM2 deficiency exacerbates macrophage apoptosis, sustains pro-inflammatory polarization, and delays wound healing.TREM2 confers radioprotection by activating ERK signaling, preserving mitochondrial integrity and suppressing caspase-dependent apoptosis.Local delivery of TREM2⁺ macrophages significantly accelerates wound repair in irradiated skin(Figure2).

Significance

This work identifies a previously unrecognized regulatory cascade:“ROS–NRF2–ADAM17–TREM2–ERK” governs macrophage fate under radiation stress. The findings provide mechanistic insight into immune dysfunction in radiation injury and highlight TREM2 as a promising therapeutic target.

Future Perspectives

Targeting TREM2 signaling or supplementing TREM2⁺ macrophages may represent novel strategies for treating radiation-induced skin injury, improving radiotherapy tolerance, and advancing regenerative medicine approaches for radiation damage.

Sources: https://spj.science.org/doi/10.34133/research.1018

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.