The glycolysis/HIF-1α axis defines the inflammatory role of IL-4-primed macrophages
Buyun Dang, Qingxiang Gao, Lishan Zhang, Jia Zhang, Hanyi Cai, Yanhui Zhu, Qiumei Zhong, Junqiao Liu, Yujia Niu, Kairui Mao, Nengming Xiao, Wen‐Hsien Liu, Shuhai Lin, Jialiang Huang, Stanley Ching‐Cheng Huang, Ping‐Chih Ho, Shih‐Chin Cheng
Abstract
T helper type 2 (Th2) cytokine-activated M2 macrophages contribute to inflammation resolution and wound healing. This study shows that IL-4-primed macrophages exhibit a stronger response to lipopolysaccharide stimulation while maintaining M2 signature gene expression. Metabolic divergence between canonical M2 and non-canonical proinflammatory-prone M2 (M2 INF ) macrophages occurs after the IL-4Rα/Stat6 axis. Glycolysis supports Hif-1α stabilization and proinflammatory phenotype of M2 INF macrophages. Inhibiting glycolysis blunts Hif-1α accumulation and M2 INF phenotype. Wdr5-dependent H3K4me3 mediates the long-lasting effect of IL-4, with Wdr5 knockdown inhibiting M2 INF macrophages. Our results also show that the induction of M2 INF macrophages by IL-4 intraperitoneal injection and transferring of M2 INF macrophages confer a survival advantage against bacterial infection in vivo . In conclusion, our findings highlight the previously neglected non-canonical role of M2 INF macrophages and broaden our understanding of IL-4-mediated physiological changes. These results have immediate implications for how Th2-skewed infections could redirect disease progression in response to pathogen infection.