Abstract 443: BAFF Neutralization Impairs The Regression Of Insulin Resistance In Diabetic Mice By Modulating The Innate Immune Response

Abstract

Adults with type 2 diabetes have a two-to-three-fold increased risk of cardiovascular diseases. B cell activating factor (BAFF), a tumor necrosis factor superfamily member, is implicated both in diabetes and cardiovascular diseases, and hence a therapeutic target of interest. High levels of BAFF are known to promote autoantibody synthesis and autoimmune diseases. We examined if BAFF neutralization with an anti-BAFF antibody improves glucose intolerance in a model of regression of insulin resistance in diabetic mice. Male C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks and segregated into two groups based on their glucose intolerance determined by a glucose tolerance test. Each group was simultaneously switched from HFD to a normal chow diet and received injections of anti-BAFF or an isotype control antibody every 2 nd week for a total of 6 weeks. As expected, body weights decreased in both groups parallel with the increase in insulin sensitivity. Unexpectedly, the BAFF-neutralized mice had impaired regression of insulin resistance compared to the control mice. Extensive cellular phenotyping of immune cells indicated systemic depletion of only the B2 cells and lower levels of circulating autoantibodies in the BAFF-neutralized mice. Gonadal white adipose tissue (gWAT) was the primary source of BAFF, and no differences in the M1 and M2 macrophages, eosinophils, natural killer cells, helper T cells, and cytotoxic T cell populations were found. RNA sequencing analysis of stromal vascular fraction from gWAT revealed impaired B cell receptor signaling, immunoglobulin production, complement activation, and phagocytosis pathways in the BAFF-neutralized mice. In this line, (i) an increased number of dead adipocytes, (ii) decreased levels of IgG2b and IgM, (iii) increased citrullinated histone H3, neutrophils, and DNA extracellular traps were found in the gWAT of BAFF-neutralized mice. These results suggest attenuated humoral response and a dominant and harmful role of innate response in the gWAT following BAFF neutralization in late-stage obesity. Since anti-BAFF biologics are approved for the treatment of lupus patients, our results highlight the need for further studies on the role of BAFF in late-stage obesity and diabetes.