Abstract
AIMS: In the context of atherosclerosis, macrophages exposed to oxidized low-density lipoproteins (oxLDLs) exhibit cellular abnormalities, specifically in adhesome functions, yet the mechanisms and implications of these adhesive dysfunctions remain largely unexplored. METHODS AND RESULTS: This study reveals a significant depletion of Kindlin3 (K3) or Fermt3, an essential component of the adhesome regulating integrin functions, in macrophages located within atherosclerotic plaques in vivo and following oxLDL exposure in vitro. To examine the effects of K3 deficiency, the study utilized hyperlipidaemic bone marrow chimeras devoid of myeloid Kindlin3 expression. The absence of myeloid K3 increased atherosclerotic plaque burden in the aortas in vivo and enhanced lipid accumulation and lipoprotein uptake in macrophages from Kindlin3-null chimeric mice in vitro. Importantly, re-expression of K3 in macrophages ameliorated these abnormalities. RNA sequencing of bone marrow-derived macrophages (BMDM) from K3-deficient mice revealed extensive deregulation in adhesion-related pathways, echoing changes observed in wild-type cells treated with oxLDL. Notably, there was an increase in Olr1 expression [encoding the lectin-like oxidized LDL receptor-1 (LOX1)], a gene implicated in atherogenesis. The disrupted K3-integrin axis in macrophages led to a significant elevation in the LOX1 receptor, contributing to increased oxLDL uptake and foam cell formation. Inhibition of LOX1 normalized lipid uptake in Kindlin3-null macrophages. A similar proatherogenic phenotype, marked by increased macrophage LOX1 expression and foam cell formation, was observed in myeloid-specific Itgβ1-deficient mice but not in Itgβ2-deficient mice, underscoring the critical role of K3/Itgβ1 interaction. CONCLUSION: This study shows that the loss of Kindlin3 in macrophages upon exposure to oxLDL leads to adhesome dysfunction in atherosclerosis and reveals the pivotal role of Kindlin3 in macrophage function and its contribution to the progression of atherosclerosis, providing valuable insights into the molecular mechanisms that could be targeted for therapeutic interventions.