Docosahexaenoic acid-derived metabolites target the B-cell driven immune response in obese mice
Crouch, Miranda Jill
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.
Crouch, Miranda Jill. (June 2019). Docosahexaenoic acid-derived metabolites target the B-cell driven immune response in obese mice (Doctoral Dissertation, East Carolina University). Retrieved from the Scholarship. (http://hdl.handle.net/10342/7239.)
Crouch, Miranda Jill. Docosahexaenoic acid-derived metabolites target the B-cell driven immune response in obese mice. Doctoral Dissertation. East Carolina University, June 2019. The Scholarship. http://hdl.handle.net/10342/7239. December 08, 2023.
Crouch, Miranda Jill, “Docosahexaenoic acid-derived metabolites target the B-cell driven immune response in obese mice” (Doctoral Dissertation., East Carolina University, June 2019).
Crouch, Miranda Jill. Docosahexaenoic acid-derived metabolites target the B-cell driven immune response in obese mice [Doctoral Dissertation]. Greenville, NC: East Carolina University; June 2019.
East Carolina University