Deletion of Talin1 in Myeloid Cells Facilitates Atherosclerosis in Mice

BACKGROUND:Integrin-regulated monocyte recruitment and cellular responses of monocyte-derived macrophages are critical for the pathogenesis of atherosclerosis. In the canonical model, talin1 controls ligand binding to integrins, a prerequisite for integrins to mediate leukocyte recruitment and induce immune responses. However, the role of talin1 in the development of atherosclerosis has not been studied. Our study investigated how talin1 in myeloid cells regulates the progression of atherosclerosis.METHODS:On an Apoe-/- background, myeloid talin1-deficient mice and the control mice were fed with a high-fat diet for 8 or 12 weeks to induce atherosclerosis. The atherosclerosis development in the aorta and monocyte recruitment into atherosclerotic lesions were analyzed.RESULTS:Myeloid talin1 deletion facilitated the formation of atherosclerotic lesions and macrophage deposition in lesions. Talin1 deletion abolished integrin beta 2-mediated adhesion of monocytes but did not impair integrin alpha 4 beta 1-dependent cell adhesion in a flow adhesion assay. Strikingly, talin1 deletion did not prevent Mn2+- or chemokine-induced activation of integrin alpha 4 beta 1 to the high-affinity state for ligands. In an in vivo competitive homing assay, monocyte infiltration into inflamed tissues was prohibited by antibodies to integrin alpha 4 beta 1 but was not affected by talin1 deletion or antibodies to integrin beta 2. Furthermore, quantitative polymerase chain reaction and ELISA (enzyme-linked immunosorbent assay) analysis showed that macrophages produced cytokines to promote inflammation and the proliferation of smooth muscle cells. Ligand binding to integrin beta 3 inhibited cytokine generation in macrophages, although talin1 deletion abolished the negative effects of integrin beta 3.CONCLUSIONS:Integrin alpha 4 beta 1 controls monocyte recruitment during atherosclerosis. Talin1 is dispensable for integrin alpha 4 beta 1 activation to the high-affinity state and integrin alpha 4 beta 1-mediated monocyte recruitment. Yet, talin1 is required for integrin beta 3 to inhibit the production of inflammatory cytokines in macrophages. Thus, intact monocyte recruitment and elevated inflammatory responses cause enhanced atherosclerosis in talin1-deficient mice. Our study provides novel insights into the roles of myeloid talin1 and integrins in the progression of atherosclerosis.