Metabolic adaption of mucosal macrophages: Is metabolism a driver of persistence across tissues?

Macrophages play essential roles in tissue homeostasis, defense, and repair. Their functions are highly tissue-specific, and when damage and inflammation stimulate repopulation by circulating monocytes, the incoming monocytes rapidly acquire the same, tissue-specific functions as the previous, resident macrophages. Several environmental factors are thought to guide the functional differentiation of recruited monocytes, including metabolic pressures imposed by the fuel sources available in each tissue. Here we discuss whether such a model of metabolic determinism can be applied to macrophage differentiation across barrier sites, from the lung to the skin. We suggest an alternative model, in which metabolic phenotype is a consequence of macrophage longevity rather than an early driver of tissue-specific adaption. Macrophages play essential roles in tissue homeostasis, defense, and repair. Their functions are highly tissue-specific, and when damage and inflammation stimulate repopulation by circulating monocytes, the incoming monocytes rapidly acquire the same, tissue-specific functions as the previous, resident macrophages. Several environmental factors are thought to guide the functional differentiation of recruited monocytes, including metabolic pressures imposed by the fuel sources available in each tissue. Here we discuss whether such a model of metabolic determinism can be applied to macrophage differentiation across barrier sites, from the lung to the skin. We suggest an alternative model, in which metabolic phenotype is a consequence of macrophage longevity rather than an early driver of tissue-specific adaption. Macrophages are cells with multiple functions: they are phagocytes, engulfing and destroying microbial pathogens, clearing immune debris and apoptotic bodies1Wynn T.A. Chawla A. Pollard J.W. 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Depending on the tissue anatomy, these resident macrophages can be replaced gradually by monocyte-derived cells that differentiate in the steady state to maintain local populations. More extreme replacement occurs in inflammation, infection, and/or immune pathology, which significantly deplete resident macrophage populations leading to an influx of monocyte-derived replacements4Ginhoux F. Guilliams M. Tissue-resident macrophage ontogeny and homeostasis.Immunity. 2016; 44: 439-449Abstract Full Text Full Text PDF PubMed Scopus (992) Google Scholar, 5Blériot C. Chakarov S. Ginhoux F. Determinants of resident tissue macrophage identity and function.Immunity. 2020; 52: 957-970Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar. 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This differentiation process suggests that a program of tissue-specific education instructs the incoming cells, determining their final function. A current hypothesis is that these tissue-specific signals are largely metabolic, with access to specific energy sources determining the possible routes of differentiation11Caputa G. Castoldi A. Pearce E.J. Metabolic adaptations of tissue-resident immune cells.Nat. Immunol. 2019; 20: 793-801Crossref PubMed Scopus (78) Google Scholar, 12Wculek S.K. Dunphy G. Heras-Murillo I. Mastrangelo A. Sancho D. Metabolism of tissue macrophages in homeostasis and pathology.Cell. Mol. Immunol. 2022; 19: 384-408Crossref PubMed Scopus (39) Google Scholar, 13Jung J. Zeng H. Horng T. Metabolism as a guiding force for immunity.Nat. Cell Biol. 2019; 21: 85-93Crossref PubMed Scopus (154) Google Scholar. This model is well accepted in the lung, where the lipid-rich environment is associated with fatty acid oxidation and pro-repair or type 2-polarized macrophage function14Svedberg F.R. et al.The lung environment controls alveolar macrophage metabolism and responsiveness in type 2 inflammation.Nat. Immunol. 2019; 20: 571-580Crossref PubMed Scopus (101) Google Scholar. Here we discuss how this paradigm applies to other barrier tissues by focusing on the skin and where and whether metabolism the tissue-specific differentiation or tissue and metabolism as of a cell and macrophage in the and a cell and on the and to the hypothesis that metabolism not confer macrophage is an for and longevity that is across and other barrier We current in the metabolic of macrophage function. 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