TREM2 Recognition of Candidalysin Orchestrates Mucosal Immunity in Oropharyngeal Candidiasis

Abstract The landscape of oral mucosal immunity, particularly in the context of oropharyngeal candidiasis (OPC), remains largely uncharted. By employing single-cell RNA sequencing (scRNA-seq) on murine models of OPC, we have illuminated the immune dynamics within this niche. We discovered a new subpopulation: TREM2-expressing macrophages, intrinsic to the oral mucosa, which infiltrated in response to Candida albicans (C. albicans) infection. However, these macrophages were significantly depleted under cortisone acetate (CA)-induced immunosuppression. This study unveiled the pattern recognition receptor (PRR) characteristics of TREM2 during OPC, where TREM2 demonstrated the ability to directly recognize candidalysin at positions G65, N73, and N91-K92, inducing downstream inflammatory signaling regulation of TNF-α, which orchestrated macrophage and neutrophil responses and influenced Th17 cell differentiation. As a result, the absence of TREM2 increases the susceptibility of mice to OPC. Conversely, administering TREM2 agonists has been shown to facilitate the clearance of OPC induced by CA in mice. Therefore, our findings expand the understanding of TREM2 beyond its known association with neurodegenerative diseases and metabolic disorders, positioning it as a key receptor in bridging the host-fungus immune interface, and providing novel therapeutic insights for glucocorticoid-induced OPC.