Frontline Science: A reduction in DHA-derived mediators in male obesity contributes toward defects in select B cell subsets and circulating antibody. Issue 2 (21st December 2018)

• Record Type: Journal Article
• Authors: Crouch, Miranda J; Kosaraju, Rasagna; Guesdon, William; Armstrong, Michael; Reisdorph, Nichole; Jain, Raghav; Fenton, Jenifer; Shaikh, Saame Raza
• Is Part Of: Journal of leukocyte biology. Volume 106:Issue 2(2019)
• Page Start: 241
• Page End: 257
• Publication Date: 2018-12-21
• Subjects: n-3 polyunsaturated fatty acids -- 14-HDHA -- 17-HDHA -- PDX; Leucocytes -- Periodicals; Reticulo-endothelial system -- Periodicals; 571.96
• DOI: 10.1002/JLB.3HI1017-405RR
• Languages: English
• ISSNs: 0741-5400

Abstract

Abstract: Obesity dysregulates B cell populations, which contributes toward poor immunological outcomes. We previously reported that differing B cell subsets are lowered in the bone marrow of obese male mice. Here, we focused on how lipid metabolites synthesized from docosahexaenoic acid (DHA) known as specialized pro-resolving lipid mediators (SPMs) influence specific B cell populations in obese male mice. Metabololipidomics revealed that splenic SPM precursors 14-hydroxydocosahexaenoic acid (14-HDHA), 17-hydroxydocosahexaenoic acid (17-HDHA), and downstream protectin DX (PDX) were decreased in obese male C57BL/6J mice. Simultaneous administration of these mediators to obese mice rescued major decrements in bone marrow B cells, modest impairments in the spleen, and circulating IgG2c, which is pro-inflammatory in obesity. In vitro studies with B cells, flow cytometry experiments with ALOX5 −/− mice, and lipidomic analyses revealed the lowering of 14-HDHA/17-HDHA/PDX and dysregulation of B cell populations in obesity was driven indirectly via B cell extrinsic mechanisms. Notably, the lowering of lipid mediators was associated with an increase in the abundance of n -6 polyunsaturated fatty acids, which have a high affinity for SPM-generating enzymes. Subsequent experiments revealed female obese mice generally maintained the levels of SPM precursors, B cell subsets, and antibody levels. Finally, obese human females had increased circulating plasma cells accompanied by ex vivo B cell TNFα and IL-10 secretion. Collectively, the data demonstrate that DHA-derived mediators of the SPM pathway control the number of B cell subsets and pro-inflammatory antibody levels in obese male but not female mice through a defect that is extrinsic to B cells. Graphical Abstract: DHA-derived mediators increase select B cell subset numbers and lower circulating pathogenic IgG2c in obese male mice.