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Nat Immunol. 2014 May;15(5):423-30. doi: 10.1038/ni.2865. Epub 2014 Mar 30.

Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin.

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  • 11] 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].
  • 21] Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, Cologne, Germany. [2].
  • 3Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, Cologne, Germany.
  • 41] 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.
  • 5Cardiovascular Research Institute, Departments of Physiology and Medicine, University of California, San Francisco, California, USA.
  • 61] 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.
  • 71] Max Planck Institute for Neurological Research, Cologne, Germany. [2] Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, Cologne, Germany.
  • 8Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
  • 9Max Planck Institute for Biology of Ageing, Cologne, Germany.
  • 101] 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.

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.

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