Neutrophil trafficking to the site of infection requires Cpt1a-dependent fatty acid beta-oxidation

• Type of Material: Article
• Authors: Ly Pham, Vanderbilt University; Padmini Komalavilas, Vanderbilt University; Alex M Eddie, Vanderbilt University; Timothy E Thayer, Vanderbilt University; Dalton L Greenwood, Vanderbilt University; Ken Liu, Emory University; Jaclyn Weinberg, Emory University; Andrew Patterson, Vanderbilt University; Joshua P Fessel, National Institutes of Health, Bethesda; Kelli L Boyd, Vanderbilt University; Jenny C Schafer, Vanderbilt University; Jamie L Kuck, Vanderbilt University; Aaron Shaver, Vanderbilt University; David K Flaherty, Vanderbilt University; Brittany K Matlock, Vanderbilt University; Christiaan DM Wijers, Vanderbilt University; Henrique Serezani, Vanderbilt University; Dean Jones, Emory University; Evan L Brittain, Vanderbilt University; Jeffrey C Rathmell, Vanderbilt University; Michael Noto, Emory University
• Language: English
• Date: 2022-12-13
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s42003-022-04339-z
• Title of Journal or Parent Work: COMMUNICATIONS BIOLOGY
• Volume: 5
• Issue: 1
• Start Page: 1366
• End Page: 1366
• Keywords: COMMUNITY-ACQUIRED PNEUMONIA; METABOLISM; G-CSF; Life Sciences & Biomedicine - Other Topics; SURVIVAL; INFANT-MORTALITY; Biology; PHAGOCYTOSIS; ACINETOBACTER-BAUMANNII; BONE-MARROW; Life Sciences & Biomedicine; ASSOCIATION; Science & Technology; Science & Technology - Other Topics; PALMITOYLTRANSFERASE; Multidisciplinary Sciences
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Immunology; Health Sciences, Pathology; Biology, Cell; Biology, Microbiology

Abstract

Cellular 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.