TREM2 helps macrophages survive and repair radiation damaged skin

Recently, teams led by Prof. Yiming Zhang from Xinqiao Hospital, Army Medical University,Prof. Fazhi Qi from Zhongshan Hospital, Fudan University, and Prof. Junli Zhou from the Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), focused on the regulatory mechanisms of macrophage function in radiation-induced skin injury and systematically elucidated the critical role of TREM2 in maintaining macrophage survival and promoting skin repair under radiation stress. The study demonstrated that irradiation activates the ROS-NRF2-ADAM17 axis, which mediates TREM2 shedding, leading to increased macrophage apoptosis and impaired reparative function. In contrast, supplementation with TREM2⁺ macrophages markedly attenuated inflammatory responses and accelerated wound healing. These findings were published in Research under the title "TREM2 Deficiency Regulates Macrophage Apoptosis and Repair in Radiation-Induced Skin Injury."

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 identifies 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.Although 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.

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.

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.