B Cell Activity Is Impaired in Human and Mouse Obesity and Is Responsive to an Essential Fatty Acid upon Murine Influenza Infection

Abstract

Obesity is associated with increased risk for infections and poor responses to vaccinations, which may be due to compromised B-cell function. However, there is limited information about the influence of obesity on B-cell function and underlying factors that modulate B-cell responses. Therefore, we studied B-cell cytokine secretion and/or antibody production across obesity models. In obese humans, B-cell IL-6 secretion was lowered and IgM levels were elevated upon ex vivo anti-BCR/TLR9 stimulation. In murine obesity induced by a high fat diet, ex vivo IgM and IgG were elevated with unstimulated B-cells. Furthermore, the high fat diet lowered bone marrow B-cell frequency accompanied by diminished transcripts of early lymphoid commitment markers. Murine B-cell responses were subsequently investigated upon influenza A/Puerto Rico/8/34 infection using a Western diet model in the absence or presence of docosahexaenoic acid (DHA3). DHA, an essential fatty acid with immunomodulatory properties, was tested since its plasma levels are lowered in obesity. Relative to controls, mice consuming the Western diet had diminished antibody titers whereas the Western diet + DHA improved titers. Mechanistically, DHA did not directly target B-cells to elevate antibody levels. Instead, DHA increased the concentration of the downstream specialized pro-resolving lipid mediators (SPMs) 14-HDHA, 17-HDHA, and protectin DX. All three SPMs were found to be effective in elevating murine antibody levels upon influenza infection. Altogether, the results demonstrate that B-cell responses are impaired across human and mouse obesity models and show that essential fatty acid status is a factor influencing humoral immunity, potentially through an SPM-mediated mechanism.

Frontline Science: A reduction in DHA-derived mediators in male obesity contributes toward defects in select B cell subsets and circulating antibody

“…Samples were analyzed immediately or frozen at −70°C until analysis. Liquid chromatography‐mass spectrometry of SPMs was performed as previously described …”

“…Flow cytometry analyses were conducted using C57BL/6J and ALOX5 −/− mice as previously described . Briefly, 2.5 × 10 5 splenocytes and 5 × 10 5 bone marrow cells were plated on 96‐well flat bottom plates followed by one wash in PBS.…”

“…The fold change was calculated by the 2 −ΔΔCt method. GAPDH and β‐actin were the housekeeping genes used in all PCR experiments, as previously described . The primer sets used in the study are presented in Supplemental Table 1.…”

“…In humans and mice, B cell cytokine secretion and antibody production are dysregulated, which contributes toward increased susceptibility to infections and poor responses to vaccinations . At the cellular level, impairments in B cell responses of obese mice are associated with a loss of differing B cell populations that control humoral immunity …”

“…There is emerging evidence from our laboratory and others that select SPM precursors and SPMs influence B cell differentiation. To exemplify, the SPM precursors 14‐HDHA and 17‐HDHA, which are generated through the action of the 12/15 lipoxygenase using DHA as a substrate, promote B cell differentiation toward CD138 + plasma cells . DHA‐derived SPMs also suppress B cell differentiation into IgE producing cells and the arachidonic acid‐derived SPM, lipoxin A4 (LXA4), inhibits antibody production from memory B cells .…”