αMβ2 Integrin Activation Prevents Alternative Activation of Human and Murine Macrophages and Impedes Foam Cell Formation
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 β2 integrins and inside-out activation of β2 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 β2 integrins, significantly inhibited 15-LO mRNA and protein expression. In contrast, activation of β1 integrins had no effect on 15-LO expression. Analysis of integrin clustering through αM, αL, αX, and αD subunits demonstrated the pivotal role for integrin αMβ2 in inhibiting 15-LO expression. IL-13 treatment upregulates 15-LO–dependent CD36 expression on human monocytes; our studies showed that β2 integrin activation and αM 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 αM-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 αMβ2 has a regulatory and potential atheroprotective function during the alternative activation of macrophages.
- Received September 2, 2010.
- Revision received December 30, 2010.
- Accepted January 6, 2011.
- © 2011 American Heart Association, Inc.