Adiponectin pathway activation dampens inflammation and enhances alveolar macrophage fungal killing via LC3-associated phagocytosis 2232

Abstract Description Innate immunity plays a crucial role in combating Aspergillus fumigatus, a significant opportunistic fungal pathogen that poses serious risks to immunocompromised patients. Our study reveals that adiponectin (APN), an adipokine with known anti-inflammatory effects, and its receptors, AdipoR1 and AdipoR2, are indispensable for survival in a murine model of invasive aspergillosis (IA). In neutropenic mice, absence of APN led to 100% mortality, heightened fungal burden, and exacerbated inflammatory responses. We show that alveolar macrophages (AMs), critical for initial lung defense, express AdipoR1 and AdipoR2, both of which are essential for APN-mediated immune responses. In APN-deficient AMs, we observed a pronounced M1 phenotype, which correlated with reduced fungal clearance. Importantly, pharmacological activation of AdipoR1 and AdipoR2 via AdipoRon restored fungal-killing capacity in APN-/- AMs, with both receptors contributing to this effect. This enhanced clearance was linked to activation of the non-canonical LC3 autophagy pathway. Our findings highlight a distinctive vulnerability in APN-/- macrophages, where necrotic cells harbor live A. fumigatus FLARE conidia—suggesting impaired host control over pathogen viability. By activating macrophage survival, AdipoRon aids fungal clearance. These insights underline APN’s translational relevance in therapeutic modulation of macrophage function, offering new strategies to bolster immune defenses against opportunistic fungi. Funding Sources R03 AI122127, NIH-R21101620, AMERICAN LUNG ASSOCIATION – INNOVATION AWARD Topic Categories Immune Mechanisms of Human Disease (HUM)