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

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.

Fatty acid metabolism in neutrophils promotes lung damage and bacterial replication during tuberculosis

“…Previous studies have demonstrated that inhibiting fatty acid metabolism in neutrophils through CPT1a mediates an impact on neutrophil chemotaxis [39]. To investigate whether the inhibition of CPT1a by ETO in neutrophils affects their migration in response to infected macrophages, we conducted a transwell chemotaxis assay.…”

The emerging role for neutrophil mitochondrial metabolism in lung inflammation

“…Acetyl-CoA is also generated from long-chain fatty acids via mitochondrial β-oxidation (FAO) [ 53 ] . Carbon labeling experiments have demonstrated that FAO is active in neutrophils, contributes substrate to the TCA cycle, and is reduced by neutrophil activation by lipopolysaccharide (LPS) [ 34 , 54 ] . In addition, the iterative process of FAO generates NADH and FADH 2 , which may transfer electrons directly to the ETC [ 53 ] .…”

“…In addition, the iterative process of FAO generates NADH and FADH 2 , which may transfer electrons directly to the ETC [ 53 ] . FAO contributes to maintenance of the mitochondrial membrane potential as inhibition of FAO has been demonstrated to reduce the membrane potential [ 54 ] . Glutamine metabolism through glutaminolysis produces α-ketoglutarate, an intermediate in the TCA cycle [ 43 ] .…”

“…We have demonstrated that disruption of mitochondrial FAO impairs mitochondrial bioenergetics in neutrophils and reduces autocrine purinergic signal amplification, chemotaxis, and neutrophil trafficking to the lungs in the context of bacterial pneumonia. FAO inhibition resulted in a marked reduction in neutrophil accumulation in the lung, reduced inflammation, impaired clearance of multiple bacterial pathogens, and decreased survival in a mouse model of bacterial pneumonia [ 54 ] . Therefore, mitochondrial metabolism and bioenergetics are fundamental to appropriate neutrophil trafficking to the lungs in the context of an inflammatory stimulus and disrupting these processes diminishes neutrophilic lung inflammation.…”

Metabolism Shapes Immune Responses to <i>Staphylococcus aureus</i>

“…5 ). Recently, a Cpt1a variant with reduced enzymatic activity has been identified in humans and linked to susceptibility to various infections, including S. aureus [ 161 ]. Cpt1a inhibition with etomoxir increased bacterial burden in a mouse model of S. aureus pneumonia ( Fig.…”