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Because tissue interstitial fluid can become acidic during the septic response, we tested the hypothesis that low extracellular pH (pHe) can induce reversible metabolic and functional changes in peritoneal macrophages from C57BL\/6J mice. When compared with macrophages cultured at normal pHe, macrophages living in an acidic medium used less glucose and exogenous fatty acid to produce ATP. Lactate, glutamine, and de novo\u2013synthesized fatty acids supported ATP production by mitochondria that gained greater mass, maximal oxygen consumption rate, and spare respiratory capacity. The cells transitioned to an M2-like state, with altered immune responses to LPS and slightly decreased phagocytic ability, yet they regained basal energy production, normal mitochondrial function, and proinflammatory responsiveness when neutral pHe was restored. Low pHe induces changes that support macrophage survival while rendering the cells less proinflammatory (more \u201ctolerant\u201d) and less able to phagocytose bacteria. Macrophage responses to low interstitial pH may contribute to the reversible organ hypofunction and immunoparalysis noted in many patients with sepsis.<\/jats:p>","DOI":"10.4049\/jimmunol.2100014","type":"journal-article","created":{"date-parts":[[2021,6,9]],"date-time":"2021-06-09T18:40:23Z","timestamp":1623264023000},"page":"3021-3031","source":"Crossref","is-referenced-by-count":13,"title":["Extracellular Acidity Reprograms Macrophage Metabolism and Innate Responsiveness"],"prefix":"10.1093","volume":"206","author":[{"given":"Wei","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Immunology, Key Laboratory of Medical Molecular Virology (MOE, NHC, CAMS), School of Basic Medical Sciences, Fudan University , Shanghai ,","place":["China"]},{"name":"Department of Trauma-Emergency & Critical Care Medicine, Shanghai Fifth People\u2019s Hospital, Fudan University , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Le","sequence":"additional","affiliation":[{"name":"Antibacterial Host Defense Unit, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping-yuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5566-5355","authenticated-orcid":false,"given":"Xiaofang","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Immunology, Key Laboratory of Medical Molecular Virology (MOE, NHC, CAMS), School of Basic Medical Sciences, Fudan University , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7777-5574","authenticated-orcid":false,"given":"Margery","family":"Smelkinson","sequence":"additional","affiliation":[{"name":"The Biological Imaging Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyue","family":"Dong","sequence":"additional","affiliation":[{"name":"Key Laboratory of Synthetic Biology, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Synthetic Biology, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwei","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Immunology, Key Laboratory of Medical Molecular Virology (MOE, NHC, CAMS), School of Basic Medical Sciences, Fudan University , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5976-7834","authenticated-orcid":false,"given":"Paul M","family":"Hwang","sequence":"additional","affiliation":[{"name":"Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1509-1294","authenticated-orcid":false,"given":"Robert S","family":"Munford","sequence":"additional","affiliation":[{"name":"Antibacterial Host Defense Unit, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8612-3444","authenticated-orcid":false,"given":"Mingfang","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Immunology, Key Laboratory of Medical Molecular Virology (MOE, NHC, CAMS), School of Basic Medical Sciences, Fudan University , Shanghai ,","place":["China"]},{"name":"Department of Trauma-Emergency & Critical Care Medicine, Shanghai Fifth People\u2019s Hospital, Fudan University , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,6,15]]},"reference":[{"key":"2025030417503917200_r1","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1038\/nri3073","article-title":"Protective and pathogenic functions of macrophage subsets","volume":"11","author":"Murray","year":"2011","journal-title":"Nat. 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