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; Shu-Hai Lin; Jialiang Huang; Stanley Ching-Cheng Huang; Ping-Chih Ho; Shih-Chin Cheng

doi:10.1016/j.celrep.2023.112471

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

Cell Rep. 2023 May 30;42(5):112471. doi: 10.1016/j.celrep.2023.112471. Epub 2023 May 6.

Authors

Buyun Dang¹, Qingxiang Gao², Lishan Zhang², Jia Zhang², Hanyi Cai², Yanhui Zhu², Qiumei Zhong², Junqiao Liu², Yujia Niu², Kairui Mao², Nengming Xiao², Wen-Hsien Liu², Shu-Hai Lin², Jialiang Huang², Stanley Ching-Cheng Huang³, Ping-Chih Ho⁴, Shih-Chin Cheng⁵

Affiliations

¹ State Key Laboratory of Cellular Stress Biology, School of Life Science, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China; Department of Gastroenterology, The National Key Clinical Specialty, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361004, China.
² State Key Laboratory of Cellular Stress Biology, School of Life Science, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China.
³ Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
⁴ Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Vaud, Switzerland; Department of Oncology, University of Lausanne, Epalinges, Switzerland.
⁵ State Key Laboratory of Cellular Stress Biology, School of Life Science, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China; Department of Gastroenterology, The National Key Clinical Specialty, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361004, China; Department of Digestive Disease, School of Medicine, Xiamen University, Xiamen, Fujian 361004, China. Electronic address: jamescheng@xmu.edu.cn.

PMID: 37149865
DOI: 10.1016/j.celrep.2023.112471

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.

Keywords: CP: Immunology; CP: Metabolism; Hif1α; IL-4; M2 macrophage; epigenetics; glycolysis; trained immunity.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cytokines / metabolism
Glycolysis / physiology
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Inflammation / metabolism
Interleukin-4* / metabolism
Interleukin-4* / pharmacology
Intracellular Signaling Peptides and Proteins / metabolism
Macrophages* / metabolism

Substances

Interleukin-4
Cytokines
Hypoxia-Inducible Factor 1, alpha Subunit
WDR5 protein, human
Intracellular Signaling Peptides and Proteins

Grants and funding

P50 CA150964/CA/NCI NIH HHS/United States