title: Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin.
abstract: Obesity and resistance to insulin are closely associated with the development of low-grade inflammation. Interleukin 6 (IL-6) is linked to obesity-associated inflammation; however, its role in this context remains controversial. Here we found that mice with an inactivated gene encoding the IL-6Rα chain of the receptor for IL-6 in myeloid cells (Il6ra(Δmyel) mice) developed exaggerated deterioration of glucose homeostasis during diet-induced obesity, due to enhanced resistance to insulin. Tissues targeted by insulin showed increased inflammation and a shift in macrophage polarization. IL-6 induced expression of the receptor for IL-4 and augmented the response to IL-4 in macrophages in a cell-autonomous manner. Il6ra(Δmyel) mice were resistant to IL-4-mediated alternative polarization of macrophages and exhibited enhanced susceptibility to lipopolysaccharide (LPS)-induced endotoxemia. Our results identify signaling via IL-6 as an important determinant of the alternative activation of macrophages and assign an unexpected homeostatic role to IL-6 in limiting inflammation.
authors.affiliation: 1] Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, Cologne, Germany. [2] Max Planck Institute for Neurological Research, Cologne, Germany. [3] Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, Cologne, Germany. [4].
authors.forename: Jan
authors.initials: J
authors.lastname: Mauer
authors.affiliation: 1] Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, Cologne, Germany. [2].
authors.forename: Bhagirath
authors.initials: B
authors.lastname: Chaurasia
authors.affiliation: Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, Cologne, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Goldau
authors.affiliation: 1] Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, Cologne, Germany. [2] Max Planck Institute for Neurological Research, Cologne, Germany. [3] Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, Cologne, Germany.
authors.forename: Merly C
authors.initials: MC
authors.lastname: Vogt
authors.affiliation: 1] Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, Cologne, Germany. [2] Max Planck Institute for Neurological Research, Cologne, Germany. [3] Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, Cologne, Germany.
authors.forename: Johan
authors.initials: J
authors.lastname: Ruud
authors.affiliation: Cardiovascular Research Institute, Departments of Physiology and Medicine, University of California, San Francisco, California, USA.
authors.forename: Khoa D
authors.initials: KD
authors.lastname: Nguyen
authors.affiliation: 1] Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, Cologne, Germany. [2] Max Planck Institute for Neurological Research, Cologne, Germany. [3] Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, Cologne, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Theurich
authors.affiliation: 1] Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, Cologne, Germany. [2] Max Planck Institute for Neurological Research, Cologne, Germany. [3] Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, Cologne, Germany.
authors.forename: A Christine
authors.initials: AC
authors.lastname: Hausen
authors.affiliation: 1] Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, Cologne, Germany. [2] Center for Endocrinology, Diabetes and Preventive Medicine, University Hospital Cologne, Cologne, Germany. [3] Center for Molecular Medicine Cologne, Cologne, Germany.
authors.forename: Joel
authors.initials: J
authors.lastname: Schmitz
authors.affiliation: 1] Max Planck Institute for Neurological Research, Cologne, Germany. [2] Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, Cologne, Germany.
authors.forename: Hella S
authors.initials: HS
authors.lastname: Brönneke
authors.affiliation: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Emma
authors.initials: E
authors.lastname: Estevez
authors.affiliation: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Tamara L
authors.initials: TL
authors.lastname: Allen
authors.affiliation: Max Planck Institute for Biology of Ageing, Cologne, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mesaros
authors.affiliation: Max Planck Institute for Biology of Ageing, Cologne, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Partridge
authors.affiliation: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Febbraio
authors.affiliation: Cardiovascular Research Institute, Departments of Physiology and Medicine, University of California, San Francisco, California, USA.
authors.forename: Ajay
authors.initials: A
authors.lastname: Chawla
authors.affiliation: 1] Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, Cologne, Germany. [2] Max Planck Institute for Neurological Research, Cologne, Germany. [3] Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, Cologne, Germany.
authors.forename: F Thomas
authors.initials: FT
authors.lastname: Wunderlich
authors.affiliation: 1] Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, Cologne, Germany. [2] Max Planck Institute for Neurological Research, Cologne, Germany. [3] Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, Cologne, Germany. [4] Center for Endocrinology, Diabetes and Preventive Medicine, University Hospital Cologne, Cologne, Germany. [5] Center for Molecular Medicine Cologne, Cologne, Germany.
authors.forename: Jens C
authors.initials: JC
authors.lastname: Brüning
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D019446:Endotoxemia / Q000276:immunology*; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation / Q000235:genetics; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009765:Obesity / Q000276:immunology*; D019947:Receptors, Interleukin-6 / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; D019947:Receptors, Interleukin-6; D015847:Interleukin-4