title: MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis.
abstract: Atherothrombotic vascular disease is often triggered by a distinct type of atherosclerotic lesion that displays features of impaired inflammation resolution, notably a necrotic core and thinning of a protective fibrous cap that overlies the core. A key cause of plaque necrosis is defective clearance of apoptotic cells, or efferocytosis, by lesional macrophages, but the mechanisms underlying defective efferocytosis and its possible links to impaired resolution in atherosclerosis are incompletely understood. Here, we provide evidence that proteolytic cleavage of the macrophage efferocytosis receptor c-Mer tyrosine kinase (MerTK) reduces efferocytosis and promotes plaque necrosis and defective resolution. In human carotid plaques, MerTK cleavage correlated with plaque necrosis and the presence of ischemic symptoms. Moreover, in fat-fed LDL receptor-deficient (Ldlr-/-) mice whose myeloid cells expressed a cleavage-resistant variant of MerTK, atherosclerotic lesions exhibited higher macrophage MerTK, lower levels of the cleavage product soluble Mer, improved efferocytosis, smaller necrotic cores, thicker fibrous caps, and increased ratio of proresolving versus proinflammatory lipid mediators. These findings provide a plausible molecular-cellular mechanism that contributes to defective efferocytosis, plaque necrosis, and impaired resolution during the progression of atherosclerosis.
authors.forename: Bishuang
authors.initials: B
authors.lastname: Cai
authors.forename: Edward B
authors.initials: EB
authors.lastname: Thorp
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Doran
authors.forename: Brian E
authors.initials: BE
authors.lastname: Sansbury
authors.forename: Mat J A P
authors.initials: MJ
authors.lastname: Daemen
authors.forename: Bernhard
authors.initials: B
authors.lastname: Dorweiler
authors.forename: Matthew
authors.initials: M
authors.lastname: Spite
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Fredman
authors.forename: Ira
authors.initials: I
authors.lastname: Tabas
mesh_terms: D000818:Animals; D002340:Carotid Artery Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D058226:Plaque, Atherosclerotic / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D000076202:c-Mer Tyrosine Kinase
chemical_list: C573412:LDLR protein, human; D011518:Proto-Oncogene Proteins; D011973:Receptors, LDL; C097072:MERTK protein, human; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase