title: IRF5 and IRF5 Disease-Risk Variants Increase Glycolysis and Human M1 Macrophage Polarization by Regulating Proximal Signaling and Akt2 Activation.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Yale University, New Haven, CT 06510, USA.
authors.forename: Matija
authors.initials: M
authors.lastname: Hedl
authors.affiliation: Department of Internal Medicine, Yale University, New Haven, CT 06510, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Internal Medicine, Yale University, New Haven, CT 06510, USA. Electronic address: clara.abraham@yale.edu.
authors.forename: Clara
authors.initials: C
authors.lastname: Abraham
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation; D005786:Gene Expression Regulation; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D047908:Intracellular Signaling Peptides and Proteins; C498178:Irf5 protein, mouse; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D048029:TNF Receptor-Associated Factor 6; C000604754:Tifab protein, human; D000119:Acetylmuramyl-Alanyl-Isoglutamine; C494921:AKT2 protein, human; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; D051057:Proto-Oncogene Proteins c-akt; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2