title: IL-6 Regulates M2 Polarization and Local Proliferation of Adipose Tissue Macrophages in Obesity.
abstract: Obesity is associated with chronic low-grade inflammation of adipose tissue (AT) and an increase of AT macrophages (ATMs) that is linked to the onset of type 2 diabetes. We have recently shown that focal sites of inflammation around dying adipocytes, so-called crown-like structures, exhibit a unique microenvironment for macrophage proliferation. Interestingly, locally proliferating macrophages were not classically activated (M1), but they exhibited a rather alternatively activated (M2) immune phenotype. In this study, we established organotypic cell cultures of AT explants to study the impact of cytokine treatment on local ATM proliferation, without the bias of early monocyte recruitment. We show that exposure of AT to Th2 cytokines, such as IL-4, IL-13, and GM-CSF, stimulates ATM proliferation, whereas Th1 cytokines, such as TNF-α, inhibit local ATM proliferation. Furthermore, AT from obese mice exhibits an increased sensitivity to IL-4 stimulation, indicated by an increased phosphorylation of STAT6. In line with this, gene expression of the IL-4 receptor (Il4ra) and its ligand IL-13 are elevated in AT of obese C57BL/6 mice. Most importantly,Il4raexpression and susceptibility to IL-4 or IL-13 treatment depend on IL-6 signaling, which seems to be the underlying mechanism of local ATM proliferation in obesity. We conclude that IL-6 acts as a Th2 cytokine in obesity by stimulating M2 polarization and local ATM proliferation, presumably due to upregulation of the IL-4 receptor α.
authors.affiliation: Institute of Anatomy, Leipzig University, 04317 Leipzig, Germany.
authors.forename: Julia
authors.identifier: 0000-0003-0460-1092
authors.initials: J
authors.lastname: Braune
authors.affiliation: Institute of Anatomy, Leipzig University, 04317 Leipzig, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Weyer
authors.affiliation: Institute of Anatomy, Leipzig University, 04317 Leipzig, Germany.
authors.forename: Constance
authors.initials: C
authors.lastname: Hobusch
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, Cornell University, New York, NY 10065; and.
authors.forename: Jan
authors.identifier: 0000-0002-0189-5876
authors.initials: J
authors.lastname: Mauer
authors.affiliation: Max Planck Institute for Metabolism Research, 50931 Cologne, Germany.
authors.forename: Jens C
authors.initials: JC
authors.lastname: Brüning
authors.affiliation: Institute of Anatomy, Leipzig University, 04317 Leipzig, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Bechmann
authors.affiliation: Institute of Anatomy, Leipzig University, 04317 Leipzig, Germany; martin.gericke@medizin.uni-leipzig.de.
authors.forename: Martin
authors.identifier: 0000-0002-0792-5394
authors.initials: M
authors.lastname: Gericke
mesh_terms: D000273:Adipose Tissue / Q000276:immunology*; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015850:Interleukin-6 / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000276:immunology*; D059467:Transcriptome
chemical_list: D015850:Interleukin-6; C577686:interleukin-6, mouse