Blocking IL-6 trans-signaling prevents high-fat diet-induced adipose tissue macrophage recruitment but does not improve insulin resistance.
Interleukin-6 (IL-6) plays a paradoxical role in inflammation and metabolism. The pro-inflammatory effects of IL-6 are mediated via IL-6 "trans-signaling," a process where the soluble form of the IL-6 receptor (sIL-6R) binds IL-6 and activates signaling in inflammatory cells that express the gp130 but not the IL-6 receptor. Here we show that trans-signaling recruits macrophages into adipose tissue (ATM). Moreover, blocking trans-signaling with soluble gp130Fc protein prevents high-fat diet (HFD)-induced ATM accumulation, but does not improve insulin action. Importantly, however, blockade of IL-6 trans-signaling, unlike complete ablation of IL-6 signaling, does not exacerbate obesity-induced weight gain, liver steatosis, or insulin resistance. Our data identify the sIL-6R as a critical chemotactic signal for ATM recruitment and suggest that selectively blocking IL-6 trans-signaling may be a more favorable treatment option for inflammatory diseases, compared with current treatments that completely block the action of IL-6 and negatively impact upon metabolic homeostasis.
Cellular and Molecular Metabolism Laboratory, BakerIDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia.
Michael J
MJ
Kraakman
Cellular and Molecular Metabolism Laboratory, BakerIDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia.
Helene L
HL
Kammoun
Cellular and Molecular Metabolism Laboratory, BakerIDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia.
Tamara L
TL
Allen
Vascular Biology and Atherosclerosis Laboratory, BakerIDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia.
Virginie
V
Deswaerte
Cellular and Molecular Metabolism Laboratory, BakerIDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia.
Darren C
DC
Henstridge
Cellular and Molecular Metabolism Laboratory, BakerIDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia.
Emma
E
Estevez
Cellular and Molecular Metabolism Laboratory, BakerIDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia.
Vance B
VB
Matthews
Cellular and Molecular Metabolism Laboratory, BakerIDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia.
Bronwyn
B
Neill
Experimental Cardiology Laboratory, BakerIDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia.
David A
DA
White
Haematopoiesis and Leukocyte Biology Laboratory, BakerIDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia.
Andrew J
AJ
Murphy
Cellular and Molecular Metabolism Laboratory, BakerIDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia.
Lone
L
Peijs
Cellular and Molecular Metabolism Laboratory, BakerIDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia.
Christine
C
Yang
Cellular and Molecular Metabolism Laboratory, BakerIDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia.
Steve
S
Risis
Cellular and Molecular Metabolism Laboratory, BakerIDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia.
Clinton R
CR
Bruce
Experimental Cardiology Laboratory, BakerIDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia.
Xiao-Jun
XJ
Du
Vascular Biology and Atherosclerosis Laboratory, BakerIDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia.
Alex
A
Bobik
Cellular and Molecular Metabolism Laboratory, BakerIDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia.
Robert S
RS
Lee-Young
Metabolic and Vascular Physiology Laboratory, BakerIDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia.
Bronwyn A
BA
Kingwell
Walter & Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
Ajithkumar
A
Vasanthakumar
Walter & Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Computing and Information Systems, University of Melbourne, Parkville, VIC 3010, Australia.
Wei
W
Shi
Walter & Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
Axel
A
Kallies
Cellular and Molecular Metabolism Laboratory, BakerIDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia.
Graeme I
GI
Lancaster
Department of Biochemistry, Christian-Albrechts-Universität zu Kiel, 24098 Kiel, Germany.
Stefan
S
Rose-John
Cellular and Molecular Metabolism Laboratory, BakerIDI Heart & Diabetes Institute, Melbourne, VIC 3004, Australia. Electronic address: mark.febbraio@bakeridi.edu.au.
Mark A
MA
Febbraio
D000273:Adipose Tissue / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D007333:Insulin Resistance / Q000502:physiology*; D015850:Interleukin-6 / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050822:Cytokine Receptor gp130