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?M?? integrin activation prevents alternative activation of human and murine macrophages and impedes foam cell formation.

ABSTRACT: 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 ?(2) integrins and inside-out activation of ?(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 ?(2) integrins, significantly inhibited 15-LO mRNA and protein expression. In contrast, activation of ?(1) integrins had no effect on 15-LO expression. Analysis of integrin clustering through ?(M), ?(L), ?(X), and ?(D) subunits demonstrated the pivotal role for integrin ?(M)?(2) in inhibiting 15-LO expression. IL-13 treatment upregulates 15-LO-dependent CD36 expression on human monocytes; our studies showed that ?(2) integrin activation and ?(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 ?(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 ?(M)?(2) has a regulatory and potential atheroprotective function during the alternative activation of macrophages.

SUBMITTER: Yakubenko VP

PROVIDER: S-EPMC3080038 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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αMβ₂ integrin activation prevents alternative activation of human and murine macrophages and impedes foam cell formation.

Yakubenko Valentin P VP Bhattacharjee Ashish A Pluskota Elzbieta E Cathcart Martha K MK

Circulation research 20110120 5

<h4>Rationale</h4>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.<h4>Objective</h4>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 ac ...[more]

PMID: 21252155

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Project description:ObjectivesThe purpose of this study was to examine selective macrophage differentiation occurring in areas of intraplaque hemorrhage in human atherosclerosis.BackgroundMacrophage subsets are recognized in atherosclerosis, but the stimulus for and importance of differentiation programs remain unknown.MethodsWe used freshly isolated human monocytes, a rabbit model, and human atherosclerotic plaques to analyze macrophage differentiation in response to hemorrhage.ResultsMacrophages characterized by high expression of both mannose and CD163 receptors preferentially exist in atherosclerotic lesions at sites of intraplaque hemorrhage. These hemoglobin (Hb)-stimulated macrophages, M(Hb), are devoid of neutral lipids typical of foam cells. In vivo modeling of hemorrhage in the rabbit model demonstrated that sponges exposed to red cells showed an increase in mannose receptor-positive macrophages only when these cells contained Hb. Cultured human monocytes exposed to Hb:haptoglobin complexes, but not interleukin-4, expressed the M(Hb) phenotype and were characterized by their resistance to cholesterol loading and up-regulation of ATP-binding cassette (ABC) transporters. M(Hb) demonstrated increased ferroportin expression, reduced intracellular iron, and reactive oxygen species (ROS). Degradation of ferroportin using hepcidin increased ROS and inhibited ABCA1 expression and cholesterol efflux to apolipoprotein A-I, suggesting reduced ROS triggers these effects. Knockdown of liver X receptor alpha (LXRα) inhibited ABC transporter expression in M(Hb) and macrophages differentiated in the antioxidant superoxide dismutase. Last, LXRα luciferase reporter activity was increased in M(Hb) and significantly reduced by overnight treatment with hepcidin. Collectively, these data suggest that reduced ROS triggers LXRα activation and macrophage reverse cholesterol transport.ConclusionsHb is a stimulus for macrophage differentiation in human atherosclerotic plaques. A decrease in macrophage intracellular iron plays an important role in this nonfoam cell phenotype by reducing ROS, which drives transcription of ABC transporters through activation of LXRα. Reduction of macrophage intracellular iron may be a promising avenue to increase macrophage reverse cholesterol transport.

Dataset Information

?M?? integrin activation prevents alternative activation of human and murine macrophages and impedes foam cell formation.

Publications

αMβ₂ integrin activation prevents alternative activation of human and murine macrophages and impedes foam cell formation.

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