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Accordingly, precise mechanisms of how cells meet metabolic demands in vivo remain unknown, making it critical to assess cell function in conjunction with tissue-niche metabolites. The majority of MØ research has been performed using cultured cell lines and/or in vitro-derived BMDM. PTRMØ have a substantial glutamate-fuelled mitochondrial reserve However, upon phagocytosis or metabolic stress, pTRMØ utilise peritoneal metabolites to promote an enhancement in glutaminolysis-fuelled CII metabolism that facilitates respiratory burst required for microbial control and immune function. Resting pTRMØ are resistant to nutrient depletion and have very little basal mitochondrial complex-II (CII) activity. Here our results link the availability of peritoneal fuels and requirements for pTRMØ metabolic processes that sustain respiratory burst. Although respiratory burst and the related signalling mechanisms are understood in neutrophils, the metabolic requirements of respiratory burst are not clear in TRMØ. These receptors engage microbes to promote phagocytosis and assembly of NADPH oxidase (NOX) 2 that supports oxidative respiratory burst 22. TRMØ express a repertoire of pattern-recognition receptors, including Dectin-1 21, mannose receptor and multiple toll-like receptors. However, TRMØ are also the front-line immune sentinels that possess primary macrophage functions including phagocytosis and respiratory burst 20. For example, pTRMØ invade peritoneal organs and facilitate repair 19, supporting their physiological importance. Macrophage biology encompasses common and tissue-niche functions. By contrast, little is known about TRMØ metabolism, or which fuels are available in tissue-niches that govern cell function 2. However, M2 differentiation itself does not require long-chain fatty acid oxidation 17, 18. In bone marrow-derived macrophages (BMDM), M1 macrophage differentiation in vitro and functions, including cytokine production, are dependent on glucose and glutamine metabolism, whereas the M2 phenotype reportedly relies on fatty acid oxidation for oxidative phosphorylation (OXPHOS), and on glutamine for protein modifications 15, 16.
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There has been resurgent interest in metabolic control of cellular function, particularly in immunology 13, 14, 15. However, the metabolic repertoire of in situ environments are largely unknown, and it is likely that other metabolites will govern resident cell functions in their respective tissues 2. The precise factors responsible for this in situ programming are largely uncategorised, although peritoneal retinoic acid can induce Gata6 expression 10 to dictate pTRMØ phenotype 10, 11, 12. It has been shown that tissue-niche environments can govern cell phenotype via epigenetic programming 8, 9. These cells exist in complex environments and do not fit traditional polarisation categories, such as LPS and interferon-γ stimulated pro-inflammatory (M1) and interleukin-4 stimulated anti-inflammatory (M2) 2, 7. Like many TRMØ, peritoneal TRMØ (pTRMØ) are not originally derived from monocytes, but rather from embryonic progenitors seeded into tissues before birth, with the populations maintained by local proliferation 3, 4, 5, 6. Tissue-resident macrophages (TRMØ) are tissue-specialised immune sentinels, which have key functions in homoeostasis and inflammation 1, 2. We propose that tissue-resident macrophages are metabolically poised in situ to protect and exploit their tissue-niche by utilising locally available fuels to implement specific metabolic programmes upon microbial sensing. In addition, we find that peritoneal-resident macrophage mitochondria are recruited to phagosomes and produce mitochondrially derived reactive oxygen species, which are necessary for microbial killing. This niche-supported, inducible mitochondrial function is dependent on protein kinase C activity, and is required to fine-tune the cytokine responses that control inflammation. We find the peritoneum to be rich in glutamate, a glutaminolysis-fuel that is exploited by peritoneal-resident macrophages to maintain respiratory burst during phagocytosis via enhancing mitochondrial complex-II metabolism. Here we show that macrophage metabolites are defined in a specific tissue context, and these metabolites are crucially linked to tissue-resident macrophage functions. The importance of metabolism in macrophage function has been reported, but the in vivo relevance of the in vitro observations is still unclear.