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

Jan Mauer, Bhagirath Chaurasia, Julia Goldau, Merly C. Vogt, Johan Ruud, Khoa D. Nguyen, Sebastian Theurich, A. Christine Hausen, Joel Schmitz, Hella S. Brönneke, Emma Estevez, Tamara L. Allen, Andrea Mesaros, Linda Partridge, Mark A. Febbraio, Ajay Chawla, Frank Thomas Wunderlich, Jens C. Brüning

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419 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)423-430
Number of pages8
JournalNature Immunology
Issue number5
Publication statusPublished - May 2014
Externally publishedYes


  • immunology

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