SREBP2 promotes macrophage alternative activation and allergic airway inflammation independent of cholesterol biosynthesis

Immunometabolic reprogramming is increasingly recognized as a critical regulator of macrophage activation and function. This study aimed to elucidate the role of the SREBP2-cholesterol biosynthetic pathway in M2 activation of interstitial macrophages (IMs) during allergic asthma. We observed a significant expansion of M2-polarized IMs with heightened SREBP2-cholesterol biosynthetic activity in the lungs of asthmatic mice. IL4, a key pro-allergic cytokine in allergic asthma, was found to induce SREBP2 maturation and activate the cholesterol biosynthetic signaling pathway in macrophages. Moreover, inhibiting SREBP2 maturation restrains IL4-induced M2 activation, both in vitro and in vivo. Intriguingly, this effect was independent of intracellular cholesterol levels; instead, cholesterol itself negatively regulated SREBP2 maturation and M2 activation. Mechanistically, mature SREBP2 transcriptional modulated IRF4 expression and interacted with it to promote IL4-induced M2 activation. Additionally, myeloid-specific Scap deficiency impeded the SREBP2 maturation process in macrophages, leading to reduced M2 activation and allergic airway inflammation. These findings highlight the pivotal role of the SREBP2-IRF4 axis in modulating M2 polarization of IMs and suggest potential therapeutic targets for asthma treatment.