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 adipokine produced mainly in adipose tissue that exerts anti-inflammatory effects in adipose-distal tissues such as the lung. 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. Pharmacological stimulation of AMs with AdipoR agonist AdipoRon partially rescued deficient killing in APN-/- AMs that was dependent on both receptors. Finally, APN-enhanced fungal killing was associated with increased activation of the non-canonical LC3 pathway of autophagy. Thus, our study identifies a novel role for APN in LC3-mediated killing of A.fumigatus. Author SummaryAspergillus fumigatus is a human fungal pathogen that causes an often-fatal invasive infection of the lung in immune compromised individuals, a population that is increasing. Since current antifungal drugs have limited efficacy, it is important to identify pathways that may be pharmaceutically targeted to complement existing therapies. Adiponectin (APN) is an anti-inflammatory intercellular cytokine messenger produced mainly in adipose tissue that protects against invasive aspergillosis. Alveolar macrophages are early immune sentinel cells in the lung, and we report that AMs from mice lacking APN exhibit an inflammatory phenotype and reduced killing of A. fumigatus spores that is improved when AMs are treated with a drug (AdipoRon) that simulates APN binding to its receptors AdipoR1 and AdipoR2. Furthermore, APN was associated with activation of LC3-associated phagocytosis, a mechanism of fungal killing important for host defense against A. fumigatus infection. Thus, we identify therapeutic potential of the APN pathway in stimulation of immune-mediated fungal killing and treatment of fungal infection.