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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #390913
Research Project: Energy Met.: Novel Approaches to Facilitating Successful Energy Regulation in Aging--Obesity & Met.: Role of Adipocyte Metabolism in the Development of Obesity and Associated Metabolic Complications

Location: Jean Mayer Human Nutrition Research Center On Aging

Title: 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

Author
item REEVES, ANDREW - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item SANSBURY, BRIAN - Harvard Medical School
item PAN, MEIXIA - University Of Texas Health Science Center
item HAN, XIANLIN - University Of Texas Health Science Center
item SPITE, MATTHEW - Harvard Medical School
item GREENBERG, ANDREW - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Journal of Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/14/2021
Publication Date: 11/1/2021
Citation: Reeves, A., Sansbury, B.E., Pan, M., Han, X., Spite, M., Greenberg, A. 2021. 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. Journal of Immunology. 207(11): 2744-2753. https://doi.org/10.4049/jimmunol.2100393.
DOI: https://doi.org/10.4049/jimmunol.2100393

Interpretive Summary: In both aging and obesity, specific immune cells synthesize and secrete molecules that activates a range of immune cells to release proteins that reduce age-associated cognition. We have demonstrated that absence of one protein within immune cells, acyl CoA synthetase 4, blocks the synthesis and secretion of these molecules that promote reductions in age-associated brain functioning. Further studies are underway to determine if absence of this protein blocks the development of age-associated decreases in cognition.

Technical Abstract: 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 Acsl4 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 Acsl4-deficient rpMACs. The Acsl4-deficient rpMACs stimulated with opZym also demonstrated an acute reduction in mRNA expression of the inflammatory cytokines, Il6, Ccl2, Nos2, and Ccl5. When Acsl4-deficient rpMACs were incubated in vitro with the TLR4 agonist, LPS, the levels of leukotriene B4 and PGE2 were also significantly decreased. In LPS-induced peritonitis, mice with myeloid-specific Acsl4 deficiency had a significant reduction in leukotriene B4 and PGE2 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 Acsl4 in rpMACs reduces the incorporation of AA into phospholipids, which reduces lipid mediator synthesis and inflammation.