An opsonic peptide promotes radiation-induced macrophage extracellular trap clearance to alleviate inflammation

Ionizing radiation exposure leads to inflammation and tissue damage, in which macrophage extracellular traps (METs) may play a role. Effective strategies to mitigate inflammation caused by radiation-induced METs are needed. We have recently developed a novel opsonic peptide, OP18, that targets multiple damage-associated molecular patterns (DAMPs) and enhances their clearance by macrophages. Because METs contain DAMPs, including histone H3 and high-mobility group box 1 protein (HMGB1), we hypothesize that OP18 promotes the clearance of radiation-induced METs and thereby reduces inflammation. In vitro studies were conducted using macrophages exposed to radiation and METs, with or without OP18 treatment. METs uptake, endo-lysosomal trafficking, integrin involvement, mitochondrial function, NF-κB activation, and cytokine release were assessed. OP18 significantly enhances MET uptake by macrophages, an effect that is mediated by α_vβ₃-integrin and involves the endo-lysosomal trafficking. This enhanced clearance by OP18 alleviates METs-induced mitochondrial stress and restores metabolic function (ATP production, basal/maximal respiration) in macrophages. Furthermore, OP18 treatment exhibits a trend towards decreasing METs-induced NF-κB activation while increasing the release of anti-inflammatory cytokine IL-10. OP18 represents a novel therapeutic approach to mitigate radiation-induced inflammation by promoting the efficient clearance of pro-inflammatory METs, thereby restoring cellular homeostasis and dampening inflammatory signaling.