Deletion of Calponin 2 in Macrophages is Anti-Inflammatory and Attenuates the Development of Atherosclerosis

Abstract

Arterial atherosclerosis is an inflammation disease. Macrophages play a central role in the pathogenesis and progression of atherosclerosis. Substrate adhesion influences macrophage differentiation into pro- or anti-inflammatory phenotypes. Calponin is an actin-filament-associated protein that inhibits myosin-ATPase and traction force, and stabilizes actin cytoskeleton and enhances cell adhesion. Encoded by the Cnn2 gene, calponin isoform 2 is expressed in macrophages. The development of atherosclerosis lesions in apolipoprotein E knockout (ApoE-/-) mice was effectively attenuated when accompanied by myeloid cell-specific Cnn2 gene knockout. Studies of peritoneal macrophages of Cnn2-/- and WT mice demonstrated that the deletion of calponin 2 increases cell motility and phagocytosis, whereas weakens cell adhesion. Cnn2-/- macrophages produced lower levels of pro-inflammatory cytokines than that in wild type macrophages. The up-regulation of pro-inflammatory cytokines in foam cells produced by loading acetylated-low-density lipoprotein in culture was also attenuated in Cnn2-/- cells. Macrophages growing on low stiffness substrate exhibit decreased calponin 2 and weakened adhesion compared to macrophages on high stiffness substrate, indicating a mechanism by which cell adhesion and mechanosignaling regulate macrophages function. Deletion of calponin 2 removes an inhibition of myosin-motors and increases the dynamics of actin cytoskeleton, which form a foundation for faster migration, enhanced phagocytosis and reduced pro-inflammatory cytokine production, corresponding to the attenuated inflammatory lesion and the development of atherosclerosis. These findings suggest a novel therapeutic approach to the treatment of coronary heart disease and other inflammatory diseases.