Adiponectin pathway activation dampens inflammation and enhances alveolar macrophage fungal killing via LC3-associated phagocytosis

Although innate immunity is critical for antifungal host defense against the human opportunistic fungal pathogen Aspergillus fumigatus, potentially damaging inflammation must be controlled. Adiponectin (APN) is an anti-inflammatory adipokine, and we observed 100% mortality and increased fungal burden and inflammation in neutropenic mice with invasive aspergillosis (IA) that lack APN or the APN receptors AdipoR1 or AdipoR2. Alveolar macrophages (AMs), early immune sentinels that detect and respond to lung infection, express both receptors, and APN-/- AMs exhibited an inflammatory/M1 phenotype that was associated with decreased fungal killing and decreased activation of LC3-associated phagocytosis (LAP). Furthermore, AM treatment with the AdipoR agonist AdipoRon partially rescued deficient killing in APN-/- AMs that was dependent on both receptors. Our study identifies a novel role for APN in LC3-mediated killing of A.fumigatus. Alveolar macrophages were isolated from adiponectin-deficient mice, cultured for ten days, treated with 20um AdipoRon or vehicle (containg DMSO) for 24 hours, then infected with swollen/fixed A. fumigatus for 12 hours at 1:1 ratio, or left uninfected. Cells were harvested and RNA isolated for bulk RNAseq.