期刊
CELL REPORTS
卷 16, 期 9, 页码 2442-2455出版社
CELL PRESS
DOI: 10.1016/j.celrep.2016.07.060
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资金
- NIH [AI110458, AI120369, DK099097, DK062422, P30-DK34989]
- Crohn's and Colitis Foundation of America
Interferon regulatory factor 5 (IRF5) regulates inflammatory M1 macrophage polarization, and disease-associated IRF5 genetic variants regulate pattern-recognition-receptor (PRR)-induced cytokines. PRR-stimulated macrophages and M1 macrophages exhibit enhanced glycolysis, a central mediator of inflammation. We find that IRF5 is needed for PRR-enhanced glycolysis in human macrophages and in mice in vivo. Upon stimulation of the PRR nucleotide binding oligomerization domain containing 2 (NOD2) in human macrophages, IRF5 binds RIP2, IRAK1, and TRAF6. IRF5, in turn, is required for optimal Akt2 activation, which increases expression of glycolytic pathway genes and HIF1A as well as pro-inflammatory cytokines and M1 polarization. Furthermore, pro-inflammatory cytokines and glycolytic pathways co-regulate each other. Rs2004640/rs2280714 TT/TT IRF5 disease-risk-carrier cells demonstrate increased IRF5 expression and increased PRR-induced Akt2 activation, glycolysis, pro-inflammatory cytokines, and M1 polarization relative to GG/CC carrier macrophages. Our findings identify that IRF5 disease-associated polymorphisms regulate diverse immunological and metabolic outcomes and provide further insight into mechanisms contributing to the increasingly recognized important role for glycolysis in inflammation.
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