Abstract 16037: Genetic Absence of the Leukocyte Integrin Mac-1 Potentiates Adipose Tissue Inflammation by Enhancing Immune Cell Infiltration
Background: Infiltration with inflammatory and immune cells is a prerequisite of adipose tissue inflammation during the metabolic syndrome. β2-integrins, such as Mac-1, are classic adhesive receptors required for efficient inflammatory cell recruitment. Here, we test whether genetic loss of Mac-1 or specific blockade of the recently described interaction of Mac-1 with CD40L affect adipose tissue inflammation in mice.
Methods and Results: WT and Mac-1-/- mice consumed a high fat diet (HFD) for 20 week (n≥15 per group). Contrasting our initial hypothesis, Mac-1-/- mice gained significantly more weight on HFD compared with respective control animals (94 ± 2.6 vs. 70 ± 2.8 % of starting body weight, p<0.001). While intraperitoneal glucose- and insulin tolerance testing showed no alteration, Mac-1 deficiency potentiated accumulation of CD11c+ M1-like macrophages and pro-inflammatory CD8+ cells by 128 ± 17.9 % and 32 ± 14 %, respectively. Furthermore, Mac-1-/- mice presented histological features of non-alcoholic liver steatosis (NASH). We previously demonstrated that the small peptide inhibitor cM7 specifically disrupts the interaction of Mac-1 with the co-stimulatory molecule CD40L. To test the specific involvement of this interaction, a second set of mice was treated with saline, cM7, or the scrambled control peptide scM7 for 20 weeks. cM7-treated animals showed no alterations in metabolic parameters, such as weight, glucose tolerance, or insulin resistance. In contrast to the genetic loss of Mac-1, adipose tissue from cM7-treated animals contained fewer CD8+ T-cells. In particular, CD8+ T-effector-memory cell counts were reduced by 37 ± 9.6 %, while numbers of macrophages and B-cells remained unaffected.
Conclusion: We present the surprising finding that genetic absence of the leukocyte integrin Mac-1 critically enhances adipose tissue inflammation during diet-induced obesity. These effects could not be attributed to the interaction with CD40L since its specific inhibition conversely ameliorated adipose tissue inflammation. These findings demonstrate that Mac-1 mediates both, inflammatory and anti-inflammatory signals during diet-induced obesity.
- © 2012 by American Heart Association, Inc.