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This phenomenon primarily has been studied in DCs from the classic laboratory inbred mouse strain C57BL\/6J (B6) mice, where DCs experience a loss of mitochondrial function due to NO accumulation. To assess the conservation of NO-driven metabolic regulation in DCs, we compared B6 mice to the wild-derived genetically divergent PWD\/PhJ (PWD) strain. We show preserved mitochondrial respiration and enhanced postactivation survival due to attenuated NO production in LPS-stimulated PWD DCs phenocopying human monocyte-derived DCs. To genetically map this phenotype, we used a congenic mouse strain (B6.PWD-Chr11.2) that carries a PWD-derived portion of chromosome 11, including Nos2, on a B6 background. B6.PWD-Chr11.2 DCs show preserved mitochondrial function and produce lower NO levels than B6 DCs. We demonstrate that activated B6.PWD-Chr11.2 DCs maintain mitochondrial respiration and TCA cycle carbon flux, compared with B6 DCs. However, reduced NO production by the PWD Nos2 allele results in impaired cellular control of Listeria monocytogenes replication. These studies establish a natural genetic model for restrained endogenous NO production to investigate the contribution of NO in regulating the interplay between DC metabolism and immune function. These findings suggest that reported differences between human and murine DCs may be an artifact of the limited genetic diversity of the mouse models used, underscoring the need for mouse genetic diversity in immunology research.<\/jats:p>","DOI":"10.4049\/jimmunol.2100375","type":"journal-article","created":{"date-parts":[[2021,12,6]],"date-time":"2021-12-06T19:25:12Z","timestamp":1638818712000},"page":"97-109","source":"Crossref","is-referenced-by-count":7,"title":["Divergent Genetic Regulation of Nitric Oxide Production between C57BL\/6J and Wild-Derived PWD\/PhJ Mice Controls Postactivation Mitochondrial Metabolism, Cell Survival, and Bacterial Resistance in Dendritic Cells"],"prefix":"10.1093","volume":"208","author":[{"given":"Julia P","family":"Snyder","sequence":"first","affiliation":[{"name":"Cell, Molecular, and Biomedical Sciences Program, University of Vermont , Burlington, VT"},{"name":"Department of Biomedical and Health Sciences, College of Nursing and Health Sciences, University of Vermont , Burlington, VT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0759-6332","authenticated-orcid":false,"given":"Soyeon K","family":"Gullickson","sequence":"additional","affiliation":[{"name":"Cell, Molecular, and Biomedical Sciences Program, University of Vermont , Burlington, VT"},{"name":"Department of Biomedical and Health Sciences, College of Nursing and Health Sciences, University of Vermont , Burlington, VT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roxana","family":"del Rio-Guerra","sequence":"additional","affiliation":[{"name":"Flow Cytometry and Cell Sorting Facility, Larner College of Medicine, University of Vermont , Burlington, VT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Sweezy","sequence":"additional","affiliation":[{"name":"Undergraduate Student Research, University of Vermont , Burlington, VT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3822-116X","authenticated-orcid":false,"given":"Bay","family":"Vagher","sequence":"additional","affiliation":[{"name":"Cell, Molecular, and Biomedical Sciences Program, University of Vermont , Burlington, VT"},{"name":"Department of Biomedical and Health Sciences, College of Nursing and Health Sciences, University of Vermont , Burlington, VT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4718-0726","authenticated-orcid":false,"given":"Tyler C","family":"Hogan","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Health Sciences, College of Nursing and Health Sciences, University of Vermont , Burlington, VT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karolyn G","family":"Lahue","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Health Sciences, College of Nursing and Health Sciences, University of Vermont , Burlington, VT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A","family":"Reisz","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, University of Colorado , Aurora, CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2258-6490","authenticated-orcid":false,"given":"Angelo","family":"D\u2019Alessandro","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, University of Colorado , Aurora, CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2709-7466","authenticated-orcid":false,"given":"Dimitry N","family":"Krementsov","sequence":"additional","affiliation":[{"name":"Cell, Molecular, and Biomedical Sciences Program, University of Vermont , Burlington, VT"},{"name":"Department of Biomedical and Health Sciences, College of Nursing and Health Sciences, University of Vermont , Burlington, VT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eyal","family":"Amiel","sequence":"additional","affiliation":[{"name":"Cell, Molecular, and Biomedical Sciences Program, University of Vermont , Burlington, VT"},{"name":"Department of Biomedical and Health Sciences, College of Nursing and Health Sciences, University of Vermont , Burlington, VT"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,1,1]]},"reference":[{"key":"2025021008470564700_r1","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/nri1391","article-title":"Toll-like receptor signalling","volume":"4","author":"Akira","year":"2004","journal-title":"Nat. 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