CTLA4-Ig treatment improves RBP4-induced adipose tissue inflammation and insulin resistance triggered by MyD88, JNK, ERK and p38 pathways (IRC8P.443)

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Abstract Adipose tissue (AT) inflammation and impaired insulin action is a major cause of type 2 diabetes. RBP4 is an adipocyte- and liver-derived protein that has an important role in insulin resistance, metabolic syndrome and AT inflammation. RBP4 elevation causes AT inflammation by activating innate immunity that elicits an adaptive immune response. Our aims are to determine the signaling pathways involved in RBP4-induced macrophage activation and the resulting antigen presentation and Th1 polarization and whether the blockade of antigen presentation improves AT inflammation and insulin resistance. RBP4-overexpressing mice (RBP4-Ox) are insulin resistant and glucose intolerant and have increased AT macrophage and Th1 cell infiltration. In RBP4-Ox, AT macrophages display enhanced JNK, ERK and p38 phosphorylation, and in vitro inhibition of these pathways reduces macrophage activation and macrophage-induced CD4 T cell proliferation and Th1 polarization. Moreover, macrophages obtained from MyD88 knockout mice and activated with RBP4 do not secrete TNF, IL12 and IL-1b and fail to induce CD4 T cell proliferation and Th1 polarization. Treatment of RBP4-Ox mice with CLTA4-Ig reduces AT inflammation and improves insulin resistance. Thus, RBP4 causes insulin resistance, at least partly, through MyD88 pathway and downstream by activating JNK, ERK and p38 pathways. These pathways induce macrophage activation and Th1 polarization, which can be blocked by inhibiting antigen presentation.