Dual role of B7 costimulation in obesity-related nonalcoholic steatohepatitis and metabolic dysregulation

Abstract

The low-grade inflammatory state present in obesity contributes to obesity-related metabolic dysregulation, including nonalcoholic steatohepatitis (NASH) and insulin resistance. Intercellular interactions between immune cells or between immune cells and hepatic parenchymal cells contribute to the exacerbation of liver inflammation and steatosis in obesity. The costimulatory molecules, B7.1 and B7.2, are important regulators of cell-cell interactions in several immune processes; however, the role of B7 costimulation in obesity-related liver inflammation is unknown. Here, diet-induced obesity (DIO) studies in mice with genetic inactivation of both B7.1 and B7.2 (double knockout; DKO) revealed aggravated obesity-related metabolic dysregulation, reduced insulin signalling in the liver and adipose tissue (AT), glucose intolerance, and enhanced progression to steatohepatitis resulting from B7.1/B7.2 double deficiency. The metabolic phenotype of B7.1/B7.2 double deficiency upon DIO was accompanied by increased hepatic and AT inflammation, associated with largely reduced numbers of regulatory T cells (Tregs) in these organs. In order to assess the role of B7 costimulation in DIO in a non-Treg-lacking environment, we performed antibody (Ab)-mediated inhibition of B7 molecules in wild-type mice in DIO. Antibodyblockade of both B7.1 and B7.2 improved the metabolic phenotype of DIO mice, which was linked to amelioration of hepatic steatosis and reduced inflammation in liver and AT. Conclusion: Our study demonstrates a dual role of B7 costimulation in the course of obesity-related sequelae, particularly NASH. The genetic inactivation of B7.1/B7.2 deteriorates obesity-related liver steatosis and metabolic dysregulation, likely a result of the intrinsic absence of Tregs in these mice, rendering DKO mice a novel murine model of NASH. In contrast, inhibition of B7 costimulation under conditions where Tregs are present may provide a novel therapeutic approach for obesityrelated metabolic dysregulation and, especially, NASH. (HEPATOLOGY 2014;60:1196-1210 O besity is associated with low-grade inflammation, liable for the development of insulin resistance (IR), type 2 diabetes, and nonalcoholic steatohepatitis (NASH). Immune cells of both innate and adaptive immunity are implicated in this process and contribute to the development of

Lymphocyte roles in metabolic dysfunction: of men and mice

“…CD80/86 co-stimulate T cells through interaction with T cell surface CD28, which in turn upregulates cytotoxic T-lymphocyte-associated protein 4 (CTLA4) to dampen sustained T cell responses [119]. Surprisingly, genetic inactivation of CD80/86 in mice promoted IR and increased AT inflammation, likely due in part to reduced anti-inflammatory Treg frequency in AT [119, 120]. However, simultaneously injecting both CD80- and CD86-blocking antibodies into wild-type DIO mice improved insulin sensitivity with no obvious impact on splenic Tregs [120], suggesting that targeting a combination of CD80 and CD86 could inhibit T2D pathogenesis.…”

“…Surprisingly, genetic inactivation of CD80/86 in mice promoted IR and increased AT inflammation, likely due in part to reduced anti-inflammatory Treg frequency in AT [119, 120]. However, simultaneously injecting both CD80- and CD86-blocking antibodies into wild-type DIO mice improved insulin sensitivity with no obvious impact on splenic Tregs [120], suggesting that targeting a combination of CD80 and CD86 could inhibit T2D pathogenesis. Future work exploring possible differences between adipocyte and macrophage CD80/86 function, as well as expansion of studies to include the long list of known co-stimulators (iCOS, PD-1 etc.…”

Adaptive Immunity and Antigen‐Specific Activation in Obesity‐Associated Insulin Resistance

“…The role of the CD80/CD86 – CD28 interaction in stimulating proliferation, survival, and memory programming of T cells has been extensively studied [25]. In obesity, CD80 and CD86 gene expression have been shown to be increased in obese human and mouse adipocytes [62, 105]. CD86+ dendritic cells were enriched in the liver and VAT of obese mice [19].…”

CD40 promotes MHC class II expression on adipose tissue macrophages and regulates adipose tissue CD4+ T cells with obesity

“…T cell costimulation is important in APC-T cell communication, and these signals are often critical nodes in the regulation of both T reg and effector/ memory T conv activity and homeostasis [18,44,45]. Because the presence or absence of appropriate costimulatory signals likely influences the magnitude of adipose tissue inflammation in obesity, many recent studies have examined the role of costimulatory molecules in this process with somewhat mixed results.…”

“…Some studies have identified a beneficial role for costimulation in maintaining a T reg pool, both systemically and in adipose tissue, which is protective against obesity-induced inflammation and metabolic disease [5,13]. In many other instances, loss of costimulation has been shown to alter energy use and inflammation in animal models [14][15][16][17][18][19].…”