Breathing and burning: metabolic control of alveolar macrophages by intracellular bacterial pathogens

Alveolar macrophages (AMs) are the lung's phagocytic immune sentinels, programmed to maintain homeostasis while defending against inhaled pathogens. AM metabolism is shaped by both developmental origin and the alveolar microenvironment. Embryonically-derived AMs populate the lungs early in life and develop into long-lived, self-renewing cells displaying lipid-centered, oxidative metabolism that restrains inflammation and preserves alveolar structure. When infection or injury disrupts homeostasis, circulating monocytes are recruited to the airspace and differentiate into monocyte-derived AMs, which adopt a glycolytic, short-lived, pro-inflammatory phenotype. Thus, differences in origin and transcriptional programming create two metabolically distinct AM populations with divergent roles in lung immunity. The intracellular bacterial pathogens Mycobacterium tuberculosis, Coxiella burnetii, Legionella pneumophila, and Francisella tularensis exploit these metabolic programs to facilitate intracellular growth and disease progression. By modulating glycolysis, remodeling mitochondria, manipulating lipid handling, or redirecting host metabolites, these pathogens evade immune insults and create growth niches. In this review, we discuss mechanisms by which AM metabolism shapes the tissue environment and pulmonary immunity, and we showcase intracellular pathogens to understand pro-bacterial reprogramming of AM metabolism.