Cholesterol sensing and metabolic adaptation in tissue immunity

Upon entry into mammalian barrier tissues such as the intestine and the lungs, immune cells are metabolically reprogrammed by the local milieu.Increased cholesterol metabolism is a feature of tissue-resident lymphocytes in the intestinal lamina propria.Chemotactic oxysterol gradients position immune cells within microanatomical niches in mucosal tissues and also drive immune cell recruitment into the respiratory tract.Recent work provides increasing evidence of the importance of cholesterol metabolism in regulating homeostatic immune function and barrier defense during infection. Immune cell function is highly regulated by cell-autonomous cholesterol metabolism; in turn, secretion of cholesterol-derived metabolites by stromal and immune cells is crucially involved in controlling mucosal immunity via cell positioning and metabolic reprogramming. An in-depth understanding of the complex crosstalk between sterols and immune cells might facilitate the development of targeted candidate therapeutics to treat both chronic and infectious diseases. Cholesterol metabolites, particularly oxidized forms known as oxysterols, play crucial roles in modulating immune and metabolic processes across various tissues. Concentrations of local cholesterol and its metabolites influence tissue-specific immune responses by shaping the metabolic and spatial organization of immune cells in barrier organs like the small intestine (SI) and lungs. We explore recent molecular and cellular evidence supporting the metabolic adaptation of innate and adaptive immune cells in the SI and lung, driven by cholesterol and cholesterol metabolites. Further research should unravel the detailed molecular mechanisms and spatiotemporal adaptations involving cholesterol metabolites in distinct mucosal tissues in homeostasis or infection. We posit that pharmacological interventions targeting the generation or sensing of cholesterol metabolites might be leveraged to enhance long-term immune protection in mucosal tissues or prevent autoinflammatory states. Cholesterol metabolites, particularly oxidized forms known as oxysterols, play crucial roles in modulating immune and metabolic processes across various tissues. Concentrations of local cholesterol and its metabolites influence tissue-specific immune responses by shaping the metabolic and spatial organization of immune cells in barrier organs like the small intestine (SI) and lungs. We explore recent molecular and cellular evidence supporting the metabo