Abstract 481: Deletion Of Talin1 In Myeloid Cells Facilitates Diet-induced Atherosclerosis

Abstract

Rationale: 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. Objective: To study the role of talin1 in myeloid cells, which include monocytes, in the progression of atherosclerosis. Methods and Results: 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. Surprisingly, myeloid talin1 deletion facilitated the formation of atherosclerotic lesion and macrophage deposition in lesions. In a flow chamber assay, talin1 deletion abolished integrin β2-mediated adhesion of monocytes but did not impair integrin α4β1-dependent cell adhesion. Strikingly, talin1 deletion did not prevent Mn 2+ - or chemokine-induced activation of integrin α4β1 to the high-affinity state, which allows ligand binding to integrins. In an in vivo competitive homing assay, monocyte infiltration into inflamed tissues was prohibited by antibodies to integrin α4β1 but was not affected by talin1 deletion or antibodies to integrin β2. Furthermore, quantitative PCR and ELISA analysis showed that ligand binding to integrin β3 inhibited macrophages to produce inflammatory cytokines. Talin1 deletion abrogated the negative regulation of integrin β3 in cytokine generation. Conclusions: Integrin α4β1 controls monocyte recruitment during atherosclerosis. Talin1 is dispensable for integrin α4β1 activation to the high-affinity state and integrin α4β1-mediated monocyte adhesion. Thus, talin1 deletion does not impair monocyte recruitment during atherosclerosis. However, talin1 deficiency abolishes the negative regulation of inflammatory cytokine production by macrophage integrin β3, leading to enhanced atherosclerosis. Our study provides novel insights into the roles of myeloid talin1 and integrins in the progression of atherosclerosis.