Neutrophil trafficking to the site of infection requires Cpt1a-dependent fatty acid β-oxidation
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Published:2022-12-13
Issue:1
Volume:5
Page:
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ISSN:2399-3642
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Container-title:Communications Biology
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language:en
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Short-container-title:Commun Biol
Author:
Pham Ly, Komalavilas Padmini, Eddie Alex M., Thayer Timothy E., Greenwood Dalton L.ORCID, Liu Ken H., Weinberg Jaclyn, Patterson Andrew, Fessel Joshua P.ORCID, Boyd Kelli L., Schafer Jenny C., Kuck Jamie L., Shaver Aaron C., Flaherty David K., Matlock Brittany K., Wijers Christiaan D. M.ORCID, Serezani C. Henrique, Jones Dean P.ORCID, Brittain Evan L.ORCID, Rathmell Jeffrey C.ORCID, Noto Michael J.
Abstract
AbstractCellular metabolism influences immune cell function, with mitochondrial fatty acid β-oxidation and oxidative phosphorylation required for multiple immune cell phenotypes. Carnitine palmitoyltransferase 1a (Cpt1a) is considered the rate-limiting enzyme for mitochondrial metabolism of long-chain fatty acids, and Cpt1a deficiency is associated with infant mortality and infection risk. This study was undertaken to test the hypothesis that impairment in Cpt1a-dependent fatty acid oxidation results in increased susceptibility to infection. Screening the Cpt1a gene for common variants predicted to affect protein function revealed allele rs2229738_T, which was associated with pneumonia risk in a targeted human phenome association study. Pharmacologic inhibition of Cpt1a increases mortality and impairs control of the infection in a murine model of bacterial pneumonia. Susceptibility to pneumonia is associated with blunted neutrophilic responses in mice and humans that result from impaired neutrophil trafficking to the site of infection. Chemotaxis responsible for neutrophil trafficking requires Cpt1a-dependent mitochondrial fatty acid oxidation for amplification of chemoattractant signals. These findings identify Cpt1a as a potential host determinant of infection susceptibility and demonstrate a requirement for mitochondrial fatty acid oxidation in neutrophil biology.
Funder
U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute
Publisher
Springer Science and Business Media LLC
Subject
General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)
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