Myeloid-Specific Deficiency of Long-Chain Acyl CoA Synthetase 4 Reduces Inflammation by Remodeling Phospholipids and Reducing Production of Arachidonic Acid-Derived Proinflammatory Lipid Mediators

In response to infection or tissue damage, resident peritoneal macrophages (rpMACs) produce inflammatory lipid mediators from the polyunsaturated fatty acid (PUFA), arachidonic acid (AA). Long-chain acyl-CoA synthetase 4 (ACSL4) catalyzes the covalent addition of a CoA moiety to fatty acids, with a...

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Veröffentlicht in:The Journal of immunology (1950) 2021-12, Vol.207 (11), p.2744-2753
Hauptverfasser: Reeves, Andrew R, Sansbury, Brian E, Pan, Meixia, Han, Xianlin, Spite, Matthew, Greenberg, Andrew S
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Sprache:eng
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Zusammenfassung:In response to infection or tissue damage, resident peritoneal macrophages (rpMACs) produce inflammatory lipid mediators from the polyunsaturated fatty acid (PUFA), arachidonic acid (AA). Long-chain acyl-CoA synthetase 4 (ACSL4) catalyzes the covalent addition of a CoA moiety to fatty acids, with a strong preference for AA and other PUFAs containing three or more double bonds. PUFA-CoA can be incorporated into phospholipids, which is the source of PUFA for lipid mediator synthesis. In this study, we demonstrated that deficiency of in mouse rpMACs resulted in a significant reduction of AA incorporated into all phospholipid classes and a reciprocal increase in incorporation of oleic acid and linoleic acid. After stimulation with opsonized zymosan (opZym), a diverse array of AA-derived lipid mediators, including leukotrienes, PGs, hydroxyeicosatetraenoic acids, and lipoxins, were produced and were significantly reduced in -deficient rpMACs. The -deficient rpMACs stimulated with opZym also demonstrated an acute reduction in mRNA expression of the inflammatory cytokines, , , , and When -deficient rpMACs were incubated in vitro with the TLR4 agonist, LPS, the levels of leukotriene B and PGE were also significantly decreased. In LPS-induced peritonitis, mice with myeloid-specific deficiency had a significant reduction in leukotriene B and PGE levels in peritoneal exudates, which was coupled with reduced infiltration of neutrophils in the peritoneal cavity as compared with wild-type mice. Our data demonstrate that chronic deficiency of in rpMACs reduces the incorporation of AA into phospholipids, which reduces lipid mediator synthesis and inflammation.
ISSN:0022-1767
1550-6606
1550-6606
DOI:10.4049/jimmunol.2100393