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

Dennis Wolf, Nora Bukosza, David Enge, Marjorie Poggi, Felix Jehle, Nathaly Anto Michel, Yung-Chih Chen, Christian Colberg, Natalie Hoppe, Bianca Dufner, Louis Boon, Hermann Blankenbach, Ingo Hilgendorf, Constantin Von Zur Muhlen, Jochen Reinoehl, Bjoern Sommer, Timoteo Marchini, Mark A. Febbraio, Christian Weber, Christoph BodeKarlheinz Peter*, Esther Lutgens, Andreas Zirlik

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Cell accumulation is a prerequisite for adipose tissue inflammation. The leukocyte integrin Mac-1 (CD11b/CD18, alpha(M)beta(2)) 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). C57BI6/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.

Original languageEnglish
Pages (from-to)325-338
Number of pages14
JournalThrombosis and Haemostasis
Volume117
Issue number2
DOIs
Publication statusPublished - Feb 2017

Keywords

  • Obesity
  • metabolic disorders
  • inflammation
  • macrophage
  • adhesion molecules
  • INSULIN-RESISTANCE
  • METABOLIC-SYNDROME
  • HEPATIC STEATOSIS
  • INTEGRIN MAC-1
  • TRANSENDOTHELIAL MIGRATION
  • ADHESION RECEPTORS
  • CELL-ADHESION
  • IMMUNE-SYSTEM
  • IN-VIVO
  • ATHEROSCLEROSIS

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