Abstract
The co-stimulatory CD40-CD40L dyad plays a central role in fine-tuning immune reactions, including obesity-induced inflammation. Genetic ablation of CD40L reduced adipose tissue inflammation, while absence of CD40 resulted in aggravated metabolic dysfunction in mice. During obesity, CD40 expressing CD11c+ dendritic cells (DC) and macrophages accumulate in adipose tissue and liver. We investigated the role of CD40+CD11c+ cells in the metabolic syndrome and nonalcoholic steatohepatitis (NASH). DC-CD40-ko mice (CD40fl/flCD11ccre) mice were subjected to obesity or NASH. Obesity and insulin resistance were induced by feeding mice a 54% high fat diet (HFD). NASH was induced by feeding mice a diet containing 40% fat, 20% fructose and 2% cholesterol. CD40fl/flCD11ccre mice fed a HFD displayed increased weight gain, increased adipocyte size, and worsened insulin resistance. Moreover, CD40fl/flCD11ccre mice had higher plasma and hepatic cholesterol levels and developed profound liver steatosis. Overall, regulatory T cell numbers were decreased in these mice. In NASH, absence of CD40 on CD11c+ cells slightly decreased liver inflammation but did not affect liver lipid accumulation. Our experiments suggest that CD40 expressing CD11c+ cells can act as a double-edged sword: CD40 expressing CD11c+ cells contribute to liver inflammation during NASH but are protective against the metabolic syndrome via induction of regulatory T cells.
Highlights
Obesity is a major risk factor for a variety of diseases including cardiovascular diseases, diabetes, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH)[1]
In line with the worsened metabolic phenotype observed in CD40−/− mice on a high fat diet[10,11,12,13], we here show that HFD fed CD40fl/flCD11ccre mice become more obese than WT mice, develop hyperinsulinemia and have an increased lipid uptake in adipose tissue and liver, resulting in severe hepatic steatosis
In contrast to the phenotype observed in total body CD40-deficient mice, CD40-deficiency in CD11c+ cells did not result in a profound increase in pro-inflammatory mediators in lymphoid organs, adipose tissue or liver
Summary
Obesity is a major risk factor for a variety of diseases including cardiovascular diseases, diabetes, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH)[1]. Deficiency of CD40L in diet-induced obesity ameliorates inflammation of the adipose tissue and reduces insulin resistance and liver steatosis[8,9]. Genetic deficiency of CD40 in mice fed a high fat diet resulted in worsened insulin resistance and increased adipose tissue inflammation compared to wild-type mice[10,11,12,13]. CD40 is expressed by a variety of cell types that play a role in obesity and metabolic dysfunction including monocytes, macrophages, DCs, B cells, T cells, endothelial cells[14] and adipocytes[15]. Increased numbers of CD11c+ cells are found in the liver of mice under obese conditions[17], and liver inflammation contributes to the progression from NAFLD (defined as the presence of ≥5% of hepatic steatosis) to NASH18. During NASH, CD40 on CD11c+ cells contributes to liver inflammation
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