Mechanisms and consequences of myeloid adhesome dysfunction in atherogenesis I

Exposure of macrophages to oxLDL in vitro or to oxidized lipids-rich milieu of atherosclerotic lesions induces dysregulation of multiple cellular processes including adhesome-dependent functions. Kindlin3 (K3) is indispensable for integrin activation and is directly involved in all adhesome-dependent cell functions. In the current study, we demonstrated that disturbance of the Kindlin3-integrin axis in myeloid cells leads to proatherogenic phenotype in hyperlipidemic LDLR-/- mice. We also found that lipid accumulation in macrophages in vivo in atherosclerotic plaque and in vitro after exposure to oxLDL was associated with strongly reduced K3 protein, likely contributing to deficient adhesome function of macrophages in lesions. RNA-seq analysis of BMDM isolated from K3 mutant with disrupted Itgβ binding site revealed multiple dysregulated adhesion-related genes and pathways overlapping with ones dysregulated in WT cells after oxLDL treatment. In addition, many dysregulated genes overlapped with genes involved in atherogenesis. These included dramatically increased expression of OLR1, a gene encoding Lectin-like oxidized LDL receptor-1 (LOX1). Disturbed Kindlin3-integrin axis in macrophages leads to dramatically increased level of LOX1 receptor in macrophages, providing a mechanism for increased uptake of oxLDL and foam cell formation. A similar proatherogenic phenotype, increased macrophage LOX1 and foam cell formation, was observed in Itgβ1 deficient mice but not Itgβ2 deficient mice, indicating that lack of Kindlin3/Itgβ1 interaction can be, at least partially, responsible for the observed phenotype.