Fatty acid oxidation regulates alveolar macrophage homeostasis and resistance to infection 4350

Abstract Description Alveolar macrophages (AMs) are essential for removing excess surfactant to maintain lung homeostasis and for pulmonary antimicrobial immunity. To adapt to this lipid rich environment, AMs engage in extensive mitochondrial metabolism, which is required for their maintenance and functions. However, the metabolic mechanisms regulating mitochondrial metabolism in AMs remain largely unknown. Here we investigated the roles of carnitine palmitoyl transferase 1A (Cpt1a), which facilitates entry of long-chain fatty acids into the mitochondria for fatty acid oxidation (FAO), in regulating AM metabolism, maintenance and function. We found that Cpt1a deficiency resulted in significantly reduced AM numbers in vivo at homeostasis. Mechanistically, transcriptomic and metabolic analyses revealed a shift towards glutamine metabolism in Cpt1a deficient AMs, which leads to the activation of mTORC1 and enhanced protein translation. These further trigger chronic endoplasmic reticulum- and integrated-stress responses in Cpt1a deficiency AMs and cause cell death. Moreover, during Mycobacterium tuberculosis (Mtb) infection, FAO deficiency in AMs promotes anti-Mtb responses at early-stage infection. Altogether, our data underscore the critical role of FAO in maintaining the AM pool by promoting adaptation of AMs to the tissue environment at homeostasis, and contributing to AM permissiveness to Mtb infection, implicating its potential as a target for host-directed therapeutics in pulmonary diseases. Funding Sources Supported by NIH/NIAID R01AI184960; R21AI175738. Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)