alpha(M)beta(2) Integrin Activation Prevents Alternative Activation of Human and Murine Macrophages and Impedes Foam Cell Formation

作者：Yakubenko Valentin P^*; Bhattacharjee Ashish; Pluskota Elzbieta; Cathcart Martha K

来源：Circulation Research, 2011, 108(5): 544-554.

DOI：10.1161/CIRCRESAHA.110.231803

• integrin alpha(M)beta(2) (CD11b/CD18)
• 15-lipoxygenase
• CD36
• M2 macrophages
• atherosclerosis

Rationale: The alternative activation of monocytes by interleukin (IL)-13 and IL-4 is a significant component of the inflammatory response. The consequences of alternative activation in inflammatory diseases remain to be determined.
Objective: In this report, we explored how integrins, receptors important for monocyte migration to inflammatory sites, regulate IL-13-mediated monocyte activation. We focused on the analysis of 2 proteins, which are upregulated during the alternative activation and are important for the development of atherosclerosis, an oxidative enzyme 15-lipoxygenase (15-LO) and a scavenger receptor CD36.
Methods and Results: We found that adhesion of resting monocytes through beta(2) integrins and inside-out activation of beta(2) integrins by monocyte chemoattractant protein-1 did not change IL-13-stimulated 15-LO upregulation; however, preincubation of monocytes with the antibody MEM48, which generates full activation of beta(2) integrins, significantly inhibited 15-LO mRNA and protein expression. In contrast, activation of beta(1) integrins had no effect on 15-LO expression. Analysis of integrin clustering through alpha(M), beta(L), alpha(X), and alpha(D) subunits demonstrated the pivotal role for integrin alpha(M)beta(2) in inhibiting 15-LO expression. IL-13 treatment upregulates 15-LO-dependent CD36 expression on human monocytes; our studies showed that beta(2) integrin activation and alpha(M) integrin clustering significantly inhibited IL-13-dependent CD36 mRNA and protein expression, as well as CD36-related foam cell formation. Moreover, IL-13 stimulation of alpha(M)-deficient peritoneal macrophages demonstrated an upregulated level of 15-LO induction, CD36 expression, and lipid accumulation as compared with wild-type controls.
Conclusions: The adhesion of monocytes/macrophages through activated integrin alpha(M)beta(2) has a regulatory and potential atheroprotective function during the alternative activation of macrophages. (Circ Res. 2011; 108: 544-554.)

• 出版日期2011-3-4