Interaction between TREM2-Macrophages and Cutibacterium acnes Drives Altered Lipid Metabolism in Chronic Apical Periodontitis

Chronic periapical periodontitis (CAP), highly prevalent worldwide, has long been regarded as non-specific inflammation. Lipophilic Cutibacerium acnes (CA) persistence in host macrophages has emerged as the pathologic background of sarcoidosis and acne vulgaris. Here we report that intracellular persistence of CA in TREM2-macrophages plays a pathologic role in CAP. We observed persistent CA in macrophages in most CAP samples. Our CA clinical isolates persist in the cytosolic space of macrophages, retarding phagolysosomal degradation accompanied by NLRP3-dependent inflammatory response. Subcutaneous injection of those isolates in vivo recapitulates subcutaneous aggregation of CA-laden macrophages. By single cell RNA sequencing analysis of defined CAP samples, we found that CA in TREM2-macrophages drives exuberant lipid droplets formation, indicating that immune cells are potential lipid provider in CAP. Our observations elucidate the mechanistic link whereby TREM2-macrophages and altered lipid metabolism provide a lipid-rich niche for CA, contributing to the pathophysiology of CAP.