Thromb Haemost 2017; 117(02): 325-338
DOI: 10.1160/TH16-07-0553
Blood Cells, Inflammation and Infection
Schattauer GmbH

Inflammation, but not recruitment, of adipose tissue macrophages requires signalling through Mac-1 (CD11b/CD18) in diet-induced obesity (DIO)

Dennis Wolf
1  Atherogenesis Research Group, University Heart Center, University of Freiburg, Freiburg, Germany
2  Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA
,
Nora Bukosza
1  Atherogenesis Research Group, University Heart Center, University of Freiburg, Freiburg, Germany
,
David Engel
3  Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands
,
Marjorie Poggi
3  Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands
,
Felix Jehle
1  Atherogenesis Research Group, University Heart Center, University of Freiburg, Freiburg, Germany
4  Atherothrombosis and Vascular Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
,
Nathaly Anto Michel
1  Atherogenesis Research Group, University Heart Center, University of Freiburg, Freiburg, Germany
,
Yung-Chih Chen
4  Atherothrombosis and Vascular Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
,
Christian Colberg
1  Atherogenesis Research Group, University Heart Center, University of Freiburg, Freiburg, Germany
,
Natalie Hoppe
1  Atherogenesis Research Group, University Heart Center, University of Freiburg, Freiburg, Germany
,
Bianca Dufner
1  Atherogenesis Research Group, University Heart Center, University of Freiburg, Freiburg, Germany
,
Louis Boon
5  EPIRUS Biopharmaceutical Netherlands, 3584 CM, Utrecht, The Netherlands
,
Hermann Blankenbach
1  Atherogenesis Research Group, University Heart Center, University of Freiburg, Freiburg, Germany
,
Ingo Hilgendorf
1  Atherogenesis Research Group, University Heart Center, University of Freiburg, Freiburg, Germany
,
Constantin von zur Muhlen
1  Atherogenesis Research Group, University Heart Center, University of Freiburg, Freiburg, Germany
,
Jochen Reinöhl
1  Atherogenesis Research Group, University Heart Center, University of Freiburg, Freiburg, Germany
,
Björn Sommer
6  Department of Neurosurgery, Medical Faculty of the Friedrich Alexander University of Erlangen-Nürnberg (FAU), Germany
,
Timoteo Marchini
1  Atherogenesis Research Group, University Heart Center, University of Freiburg, Freiburg, Germany
,
Mark A. Febbraio
7  Division of Diabetes & Metabolism, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
,
Christian Weber
8  Institute for Cardiovascular Prevention, Ludwig Maximilians University, Munich, Germany
,
Christoph Bode
1  Atherogenesis Research Group, University Heart Center, University of Freiburg, Freiburg, Germany
,
Karlheinz Peter
4  Atherothrombosis and Vascular Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
,
Esther Lutgens
8  Institute for Cardiovascular Prevention, Ludwig Maximilians University, Munich, Germany
9  Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Andreas Zirlik
1  Atherogenesis Research Group, University Heart Center, University of Freiburg, Freiburg, Germany
› Author Affiliations
Further Information

Publication History

Received:20 July 2016

Accepted after major revision:18 October 2016

Publication Date:
01 December 2017 (online)

Summary

Cell accumulation is a prerequisite for adipose tissue inflammation. The leukocyte integrin Mac-1 (CD11b/CD18, αMβ2) is a classic adhesion receptor critically regulating inflammatory cell recruitment. Here, we tested the hypothesis that a genetic deficiency and a therapeutic modulation of Mac-1 regulate adipose tissue inflammation in a mouse model of diet-induced obesity (DIO). C57Bl6/J mice genetically deficient (Mac-1-/-) or competent for Mac-1 (WT) consumed a high fat diet for 20 weeks. Surprisingly, Mac-1-/- mice presented with increased diet-induced weight gain, decreased insulin sensitivity in skeletal muscle and in the liver in insulin-clamps, insulin secretion deficiency and elevated glucose levels in fasting animals, and dyslipidaemia. Unexpectedly, accumulation of adipose tissue macrophages (ATMs) was unaffected, while gene expression indicated less inflamed adipose tissue and macrophages in Mac-1-/- mice. In contrast, inflammatory gene expression at distant locations, such as in skeletal muscle, was not changed. Treatment of ATMs with an agonistic anti-Mac-1 antibody, M1/70, induced pro-inflammatory genes in cell culture. In vivo, treatment with M1/70 induced a hyper-inflammatory phenotype with increased expression of IL-6 and MCP-1, whereas accumulation of ATMs did not change. Finally, inhibition of Mac-1’s adhesive interaction to CD40L by the peptide inhibitor cM7 did not affect myeloid cell accumulation in adipose tissue. We present the surprising finding that adhesive properties of the leukocyte integrin Mac-1 are not required for macrophage accumulation in adipose tissue. Instead, Mac-1 modulates inflammatory gene expression in macrophages. These findings question the net effect of integrin blockade in cardio-metabolic disease.

D. W., N. B., and D. E. equally contributed to this work.

K. P., E. L., and A. Z. share senior authorship.

Note: The review process for this manuscript was fully handled by Gregory Y. H. Lip, Editor in Chief.

Supplementary Material to this article is available online at www.thrombosis-online.com.