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Download fileMerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis
journal contribution
posted on 2019-03-02, 05:12 authored by Bishuang Cai, Edward B. Thorp, Amanda C. Doran, Brian E. Sansbury, Mat J.A.P. Daemen, Bernhard Dorweiler, Matthew Spite, Gabrielle Fredman, Ira TabasAtherothrombotic 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.