Antigen Presentation and T-Cell Activation Are Critical for RBP4-Induced Insulin Resistance

Author(s)

Moraes-Vieira, Pedro M. ; Castoldi, Angela ; Aryal, Pratik ; Wellenstein, Kerry ; Peroni, Odile D. ; Kahn, Barbara B. ^[1]

Affiliation

^[1] Beth Israel Deaconess Med Ctr, Dept Med, Div Endocrinol Diabet & Metab, Boston, MA 02215 - USA

• Document type: Journal article
• Source: Diabetes; v. 65, n. 5, p. 1317-1327, MAY 2016.
• Web of Science Citations: 13

Abstract

Adipose tissue (AT) inflammation contributes to impaired insulin action, which is a major cause of type 2 diabetes. RBP4 is an adipocyte- and liver-derived protein with an important role in insulin resistance, metabolic syndrome, and AT inflammation. RBP4 elevation causes AT inflammation by activating innate immunity, which elicits an adaptive immune response. RBP4-overexpressing mice (RBP4-Ox) are insulin resistant and glucose intolerant and have increased AT macrophages and T-helper 1 cells. We show that high-fat diet-fed RBP4(-/-) mice have reduced AT inflammation and improved insulin sensitivity versus wild type. We also elucidate the mechanism for RBP4-induced macrophage antigen presentation and subsequent T-cell activation. In RBP4-Ox, AT macrophages display enhanced c-Jun N-terminal kinase, extracellular signal-related kinase, and p38 phosphorylation. Inhibition of these pathways and of NF-B reduces activation of macrophages and CD4 T cells. MyD88 is an adaptor protein involved in proinflammatory signaling. In macrophages from MyD88(-/-) mice, RBP4 fails to stimulate secretion of tumor necrosis factor, IL-12, and IL-6 and CD4 T-cell activation. In vivo blockade of antigen presentation by treating RBP4-Ox mice with CTLA4-Ig, which blocks costimulation of T cells, is sufficient to reduce AT inflammation and improve insulin resistance. Thus, MyD88 and downstream mitogen-activated protein kinase and NF-B pathways are necessary for RBP4-induced macrophage antigen presentation and subsequent T-cell activation. Also, blocking antigen presentation with CTLA4-Ig improves RBP4-induced insulin resistance and macrophage-induced T-cell activation. (AU)

• FAPESP's process: 14/02218-6 - A study of the signaling pathways induced by RBP4 in macrophages and dendritic cells in obesity-induced insulin resistance
• Grantee: Angela Castoldi
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate