The glycolysis/HIF-1α axis defines the inflammatory role of IL-4-primed 2 macrophages

Abstract T helper type 2 (Th2) cytokine-activated M2 macrophages play a major role in inflammation resolution and wound healing. Myriads of studies have demonstrated the anti-inflammatory feature of M2 macrophages. In the present study, we report that IL-4-primed macrophages respond more robustly to the subsequent LPS stimulation despite maintaining the canonical M2 signature gene expression. The canonical M2 and non-canonical proinflammatory-prone macrophages (M2INF) diverge metabolically after the common IL-4Ra/Stat6 axis. While the Gln/α-KG/Jmjd3 axis is indispensable for M2 differentiation, the glycolysis/Hif-1α axis is critical for IL-4-induced M2INF. The elevated glycolysis sustains Hif-1αstabilization and the pro-inflammatory phenotype of M2INF. Conversely, inhibition of glycolysis blunts Hif-1αaccumulation and M2INF. Macrophages from myeloid-specific Hif-1α KO mice retain M2 differentiation capacity but fail to induce M2INF. Wdr5-dependent H3K4me3 epigenetic modification mediates the long-lasting effect of IL-4 as the knocking down of Wdr5 inhibits M2INF. Moreover, the induction of M2INF by IL-4 intraperitoneal injection and transferring of M2INF provides a survival advantage against bacterial infection in vivo. To conclude, our findings delineate the previously neglected non-canonical role of M2INF. This will broaden our understanding of IL-4-mediated physiological changes and provide immediate impacts on how Th2-skewed infections could re-direct disease progression in response to pathogen infection.