Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin
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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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Several studies demonstrate an anti-inflammatory role for IL6.
“On the other hand, several studies demonstrate an anti-inflammatory role for IL6 (Mauer et al., 2014; Nandi et al.).”
From Origin and function of stress-induced IL-6 in murine models (2020) · cites this paper as Mauer et al., 2014
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- Authors
- Mauer, J., Chaurasia, B., Goldau, J., Vogt, M. C., Ruud, J., Nguyen, K. D., Theurich, S., Hausen, A. C., Schmitz, J., Brönneke, H. S., Estevez, E., Allen, T. L., Mesaros, A., Partridge, L., Febbraio, M. A., Chawla, A., Wunderlich, F. T., & Brüning, J. C.
- Affiliations
- University of Cologne (DE)
- University of California, San Francisco (US)
- Max Planck Institute for Metabolism Research (DE)
- Baker Heart and Diabetes Institute (AU)
- Max Planck Institute for Biology of Ageing (DE)
- Corresponding author
- Brüning, Jens C
- ORCID
- Venue
- Nature Immunology
- Published
- 2014-03-30
- Volume
- 15
- Issue
- 5
- Pages
- 423-430
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC4161471
- OpenAlex
- W2100386453
- Cited by
- 727
- References
- 49
- Citations by year
- 2026: 18 · 2025: 39 · 2024: 48 · 2023: 47 · 2022: 61 · 2021: 79 · 2020: 74 · 2019: 64 · 2018: 67 · 2017: 70 · 2016: 67 · 2015: 53 · 2014: 25 · 2012: 1
- FWCI
- 54.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- PubMed Central (acceptedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Max Planck Digital Library (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Wellcome Trust (098565)
- National Heart, Lung, and Blood Institute (HL076746, R01HL076746)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-094641, R01DK094641)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (DP1AR064158)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- interleukin-6, IL-6 receptor alpha, macrophage polarization, alternative macrophage activation, endotoxemia, lipopolysaccharide, insulin resistance, obesity, low-grade inflammation, IL-4 receptor, glucose homeostasis, diet-induced obesity, myeloid cells
- MeSH terms
- Animals, Cells, Cultured, Humans, Insulin Resistance, Lipopolysaccharides, Macrophage Activation, Macrophages, Mice, Inbred C57BL, Mutation, Obesity, Signal Transduction, Interleukin-4, Interleukin-6, Mice, Knockout, Endotoxemia, Receptors, Interleukin-6, Mice
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