Depletion of CD40 on CD11c + cells worsens the metabolic syndrome and ameliorates hepatic inflammation during NASH

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

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 (CD40 fl/fl CD11c cre ) 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. CD40 fl/fl CD11c cre mice fed a HFD displayed increased weight gain, increased adipocyte size, and worsened insulin resistance. Moreover, CD40 fl/fl CD11c cre 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 th

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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