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

Aarts, Suzanne; Reiche, Myrthe; Toom, Myrthe den; Gijbels, Marion; Beckers, Linda; Gerdes, Norbert and Lutgens, Esther (2019): Depletion of CD40 on CD11c(+) cells worsens the metabolic syndrome and ameliorates hepatic inflammation during NASH. In: Scientific Reports, Vol. 9, 14702

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 (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 the metabolic syndrome via induction of regulatory T cells.

• Item Type: Journal article
• Faculties: Medicine
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 2045-2322
• Language: English