title: Inflammation, but not recruitment, of adipose tissue macrophages requires signalling through Mac-1 (CD11b/CD18) in diet-induced obesity (DIO).
abstract: 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.
authors.forename: Dennis
authors.initials: D
authors.lastname: Wolf
authors.forename: Nora
authors.initials: N
authors.lastname: Bukosza
authors.forename: David
authors.initials: D
authors.lastname: Engel
authors.forename: Marjorie
authors.initials: M
authors.lastname: Poggi
authors.forename: Felix
authors.initials: F
authors.lastname: Jehle
authors.forename: Nathaly
authors.initials: N
authors.lastname: Anto Michel
authors.forename: Yung-Chih
authors.initials: YC
authors.lastname: Chen
authors.forename: Christian
authors.initials: C
authors.lastname: Colberg
authors.forename: Natalie
authors.initials: N
authors.lastname: Hoppe
authors.forename: Bianca
authors.initials: B
authors.lastname: Dufner
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.forename: Hermann
authors.initials: H
authors.lastname: Blankenbach
authors.forename: Ingo
authors.initials: I
authors.lastname: Hilgendorf
authors.forename: Constantin
authors.initials: C
authors.lastname: von Zur Muhlen
authors.forename: Jochen
authors.initials: J
authors.lastname: Reinöhl
authors.forename: Björn
authors.initials: B
authors.lastname: Sommer
authors.forename: Timoteo
authors.initials: T
authors.lastname: Marchini
authors.forename: Mark A
authors.initials: MA
authors.lastname: Febbraio
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.forename: Christoph
authors.initials: C
authors.lastname: Bode
authors.affiliation: Prof. Dr. Karlheinz Peter, Atherothrombosis and Vascular Biology, Baker IDI Heart and Diabetes Institute, P. O. Box 6492. St. Kilda Road Central, Melbourne, Victoria 8008, Australia, Tel.: +61 3 8532 1490, Fax: +61 3 8532 1100, E-mail: karlheinz.peter@bakeridi.edu.au.
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Peter
authors.forename: Esther
authors.initials: E
authors.lastname: Lutgens
authors.forename: Andreas
authors.initials: A
authors.lastname: Zirlik
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D039481:CD11b Antigen / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018821:CD18 Antigens / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004032:Diet / Q000009:adverse effects*; D004195:Disease Models, Animal; D005838:Genotype; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects; D015430:Weight Gain
chemical_list: D000911:Antibodies, Monoclonal; D039481:CD11b Antigen; D018821:CD18 Antigens; D016207:Cytokines; C483346:M1-70 monoclonal antibody; D016177:Macrophage-1 Antigen
keywords: Obesity; adhesion molecules; inflammation; macrophage; metabolic disorders