Recent research led by Prof. Yiming Zhang, Prof. Fazhi Qi, and Prof. Junli Zhou has revealed critical insights into the regulatory mechanisms of macrophage function in radiation-induced skin injury.
The study, published in Research, elucidates the pivotal role of TREM2 in sustaining macrophage viability and facilitating skin repair under radiation stress. The investigation demonstrated that irradiation triggers the ROS-NRF2-ADAM17 pathway, which leads to TREM2 shedding, consequently increasing macrophage apoptosis and impairing their reparative function. Conversely, introducing TREM2+ macrophages significantly reduced inflammatory responses and expedited wound healing.
Radiation-induced skin injury (RISI) is a prevalent and debilitating side effect of radiotherapy, affecting up to 95% of cancer patients. Persistent inflammation and delayed wound healing pose significant clinical challenges, with limited effective treatments currently available. Macrophages are central to managing inflammatory responses and tissue repair, yet their regulation under radiation stress is not well understood.
Employing single-cell RNA sequencing, mouse models, and in vitro macrophage assays, the researchers identified TREM2 as a crucial regulator of macrophage survival and repair in RISI. Radiation instigates a unique TREM2+ macrophage subset that serves as a central hub in inflammatory signaling networks.
Although the transcription of TREM2 increases post-irradiation, TREM2 protein levels decline due to radiation-induced oxidative stress. Mechanistically, radiation activates the ROS-NRF2-ADAM17 axis, promoting TREM2 shedding and the release of soluble TREM2. A deficiency in TREM2 exacerbates macrophage apoptosis, perpetuates pro-inflammatory polarization, and delays wound healing.
TREM2 provides radioprotection by activating ERK signaling, preserving mitochondrial integrity, and inhibiting caspase-dependent apoptosis. Local administration of TREM2+ macrophages markedly accelerates wound repair in irradiated skin.
This study identifies a previously unrecognised regulatory cascade: “ROS-NRF2-ADAM17-TREM2-ERK” that dictates macrophage fate under radiation stress. The findings offer mechanistic insights into immune dysfunction in radiation injury and highlight TREM2 as a promising therapeutic target.
Targeting TREM2 signalling or supplementing TREM2+ macrophages could emerge as novel strategies for treating radiation-induced skin injury, enhancing radiotherapy tolerance, and advancing regenerative medicine approaches for radiation damage.
For further reading, the study can be accessed via the Science and Technology Review Publishing House or directly through the DOI: 10.34133/research.1018.
