αVβ3 integrin regulates macrophage inflammatory responses via PI3 kinase/Akt‐dependent NF‐κB activation

Abstract

Controlling macrophage responses to pathogenic stimuli is critical for prevention of and recovery from the inflammatory state associated with the pathogenesis of many diseases. The adhesion receptor αVβ3 integrin is thought to be an important receptor that regulates macrophage differentiation and macrophage responses to external signaling, but it has not been previously identified as a contributor to macrophage-related inflammation. Using an in vitro model of human blood monocytes (Mo) and monocyte-derived macrophages (MDMs) we demonstrate that αVβ3 ligation results in sustained increases of the transcription factor NF-κB DNA-binding activity, as compared with control isotype-matched IgG1. Activation of NF-κB parallels the increase of NF-κB-dependent pro-inflammatory cytokine mRNA expression in MDMs isolated from individual donors, for example, TNF-α (8- to 28-fold), IL-1β (15- to 30-fold), IL-6 (2- to 4-fold), and IL-8 (5- to 15-fold) whereas there is more than a 10-fold decrease in IL-10 mRNA level occurs. Upon ligation of the αVβ3 receptor, treatment with TNF-α (10 ng/ml) or LPS (200 ng/ml, 1,000 EU) results in the enhanced and synergistic activation of NF-κB and LPS-induced TNF-α secretion. As additional controls, an inhibitor of αVβ3 integrin, cyclic RGD (10 μg/ml; IC50 = 7.6 μM), attenuates the effects of αVβ3 ligation, and the natural ligand of αVβ3 integrin, vitronectin, reproduces the effects of αVβ3 activation by an immobilizing anti-αVβ3 integrin mAb. We hypothesize that αVβ3 activation can maintain chronic inflammatory processes in pathological conditions and that the loss of αVβ3 ligation will allow macrophages to escape from the inflammatory state.

αvβ3 Integrins Mediate Flow-Induced NF-κB Activation, Proinflammatory Gene Expression, and Early Atherogenic Inflammation

“…In addition, avb3 ligation reduces oxLDL uptake by down-regulating macrophage scavenger protein expression (CD36, SRA), suggesting that avb3 limits macrophage dysfunction in atherosclerosis. 40 However, avb3 signaling also promotes macrophage NF-kB activation and proinflammatory cytokine expression (tumor necrosis factor-a, IL-1b) in cell culture models, 42 although studies of b3-deficient macrophages are conflicting with both positive and negative effects on homing and proinflammatory gene expression described. 43e45 Smooth muscle cell avb3 ligation promotes cell proliferation and migration under several experimental conditions and reduces oxLDL-induced apoptosis.…”

ß₃-Integrin Inhibits Lipopolysaccharide-Induced Autophagy in Cardiomyocytes via the Akt Signaling Pathway

“…cRGD is a synthetic peptide containing the RGD sequence, which has been shown to compete with adhesive proteins that bind to β 3 -integrin receptors. cRGD peptide abolishes α V β 3 ligation to the extracellular matrix and the effects on the secretion of TNF-α in macrophages and interrupts the subsequent signal transduction upon β 3 -integrin ligation [19,29]. Our experiments showed that autophagy-related proteins were increased, and autophagosomes formed and accumulated in cardiomyocytes in which β 3 -integrin was blocked by cRGD.…”

“…The IκB kinase/nuclear factor-κB, mitogen-activated protein kinase and AMP-activated protein kinase pathways activate autophagy [16,17,18], while only the Akt pathway has inhibitory potential. β 3 -Integrin can also activate Akt signaling in macrophages when LPS is added and in isolated cardiomyocytes simulated by H 2 O 2 [19,20]. The focal adhesion complex, which is the downstream signaling component of integrin, directly controls the activation of Akt in response to cell-matrix adhesion [21].…”

Molecular Imaging of Vulnerable Coronary Plaque: A Pathophysiologic Perspective

“…The a v b 3 integrin is expressed on macrophages, migrating smooth muscle cells, and endothelial cells in the vasa vasorum and intraplaque microvasculature of coronary arteries (19). The tripeptide arginine-glycine-aspartic acid (RGD) has a high affinity for integrin a v b 3 and is often used as the primary binding motif in integrin-targeting imaging agents.…”