Abstract 78: Chemokine-Driven β2 Integrin Adhesion Influences Macrophage Cytokine Gene Expression and Atherosclerotic Lesion Composition Through an Induced Rac2-Myosin IIa Interaction
Chemokine-driven β2 integrin adhesion facilitates the activation and subendothelial migration of monocyte/macrophages in both acute and chronic vascular inflammatory processes. We have shown that engagement of β2 integrin contributes to stabilization of labile mRNAs encoding inflammatory cytokines (TNF-α, GM-CSF, IL-1), through translocation of the RNA binding protein HuR. These changes in cytokine gene expression influence monocyte/macrophage effector function, skewing the delicate balance between physiologic and pathologic responses. Using bone marrow-derived macrophages from wild-type and gene-deleted mice, we demonstrate that the hematopoietic cell-specific low molecular weight G protein, Rac2, is activated (GTP-bound) by β2 integrin engagement and required for effective integrin-induced nuclear-to-cytosolic HuR translocation. Moreover, this process depends on both the isoprenylation state of Rac2 and its interactions with Myosin IIA, an atypical myosin component of the cytoskeletal network. The HMG CoA reductase inhibitor atorvastatin leads to loss of Rac2 isoprenylation and consequent reduction in HuR translocation. The Myosin IIA-specific inhibitor, blebbistatin, disrupts the induced Rac2-myosin association, reduces translocation of HuR, and inhibits stabilization of cytokine mRNA. In Apo-E deficient mice, gene deletion of Rac2 influences atherosclerotic plaque composition, with more heavily calcified plaques identified by ex vivo microCT angiography. This provides evidence that Rac2’s effect on macrophage effector function influences consequential vascular pathology. In summary, chemokine-driven integrin engagement leads to isoprenylation-dependent activation of Rac2, resulting in translocation of HuR through an induced Rac2-Myosin IIA complex. This constitutes an important molecular switch in the activation of monocyte/macrophage inflammatory cascades, prolonging cytokine production and influencing the composition within vascular pathologies such as atherosclerosis. Targeting this newly identified signaling pathway has potential to yield a novel class of molecular therapeutics directed at influencing the course of vascular disease.
- © 2012 by American Heart Association, Inc.