title: Immune modulation of vascular resident cells by Axl orchestrates carotid intima-media thickening.
abstract: Cellular mechanisms of carotid intima-media thickening (IMT) are largely unknown. The receptor tyrosine kinase Axl is essential for function of both bone marrow (BM) and non-BM cells. We studied the mechanisms by which Axl expression in BM-derived cells (compared with non-BM-derived cells) mediates carotid IMT. Partial ligation of the left carotid artery resulted in a similar carotid blood flow reduction in Axl chimeras. Neither irradiation nor bone marrow transplantation had any effect on the 40% difference in carotid IMT between Axl genotypes. Axl-dependent survival is very important for intimal leukocytes; however, Axl expression in BM cells contributes to <30% of carotid IMT. Axl in non-BM cells has a greater effect on carotid remodeling. Expression of Axl in non-BM cells is crucial for the up-regulation of several key proinflammatory signals (eg, IL-1) in the carotid. We found that Axl is involved in immune activation of cultured smooth muscle cells and in immune heterogeneity of medial cells (measured by major histocompatibility complex class II) after carotid injury. Finally, a lack of Axl in non-BM cells increased collagen Iα expression, which may play a critical role in carotid remodeling. Our data suggest that Axl contributes to carotid remodeling not only by inhibition of apoptosis but also via regulation of immune heterogeneity of vascular cells, cytokine/chemokine expression, and extracellular matrix remodeling.
authors.affiliation: Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
authors.forename: Janice
authors.initials: J
authors.lastname: Gerloff
authors.forename: Vyacheslav A
authors.initials: VA
authors.lastname: Korshunov
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002339:Carotid Arteries / Q000276:immunology*; D059168:Carotid Intima-Media Thickness; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D005109:Extracellular Matrix / Q000378:metabolism; D005838:Genotype; D018836:Inflammation Mediators / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000276:immunology; D010446:Peptide Fragments / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D018183:Transplantation Chimera; D017539:Tunica Intima / Q000276:immunology; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D003094:Collagen; C045653:collagen I, alpha chain (98-110); D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; C000722290:AXL receptor tyrosine kinase, mouse