2019
Sci Rep. 2019 Oct 11;9(1):14702. doi: 10.1038/s41598-019-50976-6.
Depletion of CD40 on CD11c+ cells worsens the metabolic syndrome and ameliorates hepatic inflammation during NASH.
University of Amsterdam, Amsterdam, The Netherlands. University of Maastricht, Maastricht, The Netherlands. University Hospital Düsseldorf, Düsseldorf, Germany. Ludwig Maximilian's University (LMU), Munich, Germany.
Service type: Knockout mice
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.
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