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<p>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 <i>Scap</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月3日

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  • Yinfang Wu,
  • Kua Zheng,
  • LingLing Dong,
  • Shenwei Gao,
  • Yanping Wu,
  • Zhengyuan Liu,
  • Jieyu Li,
  • Haipin Chen,
  • Qingyu Weng,
  • Miao Li,
  • Chen Zhu,
  • Jiahuan Xu,
  • Songmin Ying,
  • Zhihua Chen,
  • Wen Li

摘要

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.