Cholesterol homeostatic regulator SREBP2 promotes macrophage alternative activation and allergic airway inflammation

ABSTRACT: Metabolic reprogramming is well-appreciated to be able to control macrophage activation. However, it remains unknown whether the SREBPs-lipogenesis pathway is involved in macrophage alternative (or M2) activation. Here, we showed that IL4-induced M2 activation was coupled with increased SREBP2 maturation and activated cholesterol biosynthetic pathway, while the SREBP1-fatty acid biosynthesis pathway remained unaffected after IL4 stimulation. Genetic or pharmacologic blockade of SREBP2 maturation significantly inhibited IL4-induced M2 activation independent of cholesterol. Instead, cholesterol inhibited M2 activation most likely through its feedback regulation of SREBP2 maturation. Mechanically, the upregulation of SREBP2 maturation was dependent on the activation of upstream MTOR, and mature SREBP2 increased the expression of KAZALD1 and subsequently activated the IGF1 signaling to promote IL4-induced M2 activation. Consistently, myeloid-specific Scap deficiency markedly decreased the number of M2 macrophages in the lung and attenuated the HDM-induced allergic airway inflammation. Taken together, these findings highlight a critical role for cholesterol homeostatic regulator SREBP2 in M2 activation, which advances our understanding of the regulation of immunometabolism for M2 activation and points to new opportunities for therapeutic control of M2 activation and allergic airway inflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE188356 | GEO | 2023/04/30

REPOSITORIES: GEO