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

Area of Science:

• Radiation oncology
• Immunology
• Wound healing

Background:

• Radiation-induced skin injury (RISI) is a significant radiotherapy complication.
• Macrophage dysfunction is central to RISI, but underlying mechanisms are unclear.
• The role of TREM2 in macrophage response to radiation requires investigation.

Purpose of the Study:

• To investigate the role of TREM2 in macrophage regulation following irradiation.
• To elucidate the molecular mechanisms governing TREM2 expression and function in irradiated macrophages.
• To explore therapeutic potential of targeting the TREM2 pathway for RISI.

Main Methods:

• Single-cell RNA sequencing and in vivo mouse models (LysM-Cre Trem2-flox/flox).
• In vitro macrophage assays assessing TREM2 protein levels, apoptosis, and polarization.
• Analysis of the ROS-NRF2-ADAM17-TREM2-ERK signaling axis.

Main Results:

• Radiation induced TREM2+ macrophages, but ADAM17-mediated shedding reduced TREM2 protein.
• Inhibiting ADAM17 restored TREM2, promoted M2 polarization, and enhanced macrophage survival.
• TREM2 deficiency worsened RISI, while TREM2 overexpression or transfer accelerated healing.
• TREM2 conferred radioprotection via ERK pathway activation.

Conclusions:

• A novel ROS-NRF2-ADAM17-TREM2-ERK cascade regulates macrophage fate in radiation stress.
• Targeting this pathway or using TREM2+ macrophages shows therapeutic promise for RISI.
• TREM2 is a critical mediator of macrophage response and tissue repair post-irradiation.