Docosahexaenoic acid-derived metabolites target the B-cell driven immune response in obese mice

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Miranda Jill Crouch (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Obesity is associated with an impaired humoral immune response. As B cells mediate the humoral immune response , they are major cellular targets in diet induced obesity models. Several studies have established that B cell function is impaired in obesity potentially due to decreased AID levels and impaired leptin signaling. Studies have also found that B cells from obese individuals secrete pro-inflammatory cytokines and that B cells seem to have a pathological role in the visceral adipose tissue in obesity. We have also established that obese mice have decreased numbers of total B cells and B cell subsets in the bone marrow compared to their control counterparts. Despite these findings , mechanisms elucidating how the B cell response is impaired are not well established. We and others have shown that specialized pro-resolving lipid mediator (SPM) precursors and SPMs are decreased in various tissues in obese humans and mice. As SPMs promote tissue homeostasis , prevent chronic inflammation , and can regulate B cell antibody production , we investigated whether deficiencies in the levels of SPM precursors and SPMs could be contributing to the impairments in B cell subsets and B cell function in obesity. We administered a cocktail of 14-HDHA/17-HDHA/PDX to obese mice for four consecutive days as these DHA-derived metabolites were decreased in the spleens of obese mice. Overall , we found that these metabolites regulate B cell numbers in various tissues in obese mice. In particular , administration of 14-HDHA/17-HDHA/PDX to obese mice rescued decrements in total B cell and B cell subset numbers in the bone marrow. Furthermore , we found that these metabolites also decreased the number of B cells in the visceral adipose tissue , which were elevated in obese mice. We hypothesize that these DHA-derived metabolites are limiting B cell recruitment to the adipose by regulating chemokine receptor interactions with their corresponding ligands as obese mice receiving the DHA-derived metabolites had decreased transcript expression of various chemokine receptors that are upregulated in obesity. Obese mice receiving the DHA-derived metabolites also had decreased levels of pathogenic IgG2c in circulation as well as decreased IgM and IgG levels in the VAT. In addition , we established that supplementation of the parent fatty acid , DHA in the diet can increase antibody production in obese mice infected with influenza. When 14-HDHA , 17-HDHA , and PDX were administered individually to lean mice infected with influenza , 14-HDHA enhanced antibody titers and the number of antibody secreting cells in the bone marrow. Interestingly , we found that SPM precursors and SPM levels were not decreased in obese female mice. The obese female mice also did not have major decrements in B cell numbers in the bone marrow and had a decreased inflammatory profile compared to their male counterparts. Overall , findings from this dissertation propose that administration of DHA-derived metabolites that are deficient in obese mice can regulate B cell numbers across various tissues , potentially modulate the pro-inflammatory B cell phenotype in the adipose tissue , and enhance antibody production in the context of influenza.

Additional Information

Publication

Dissertation

Language: English

Date: 2019

Keywords

humoral immunity, SPMs, antibody, metabolism

Subjects

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