MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis
Bishuang Cai, Edward B. Thorp, Amanda C. Doran, Brian E. Sansbury, Mat J.A.P. Daemen, Bernhard Dorweiler, Matthew Spite, Gabrielle Fredman, Ira Tabas
Bishuang Cai, Edward B. Thorp, Amanda C. Doran, Brian E. Sansbury, Mat J.A.P. Daemen, Bernhard Dorweiler, Matthew Spite, Gabrielle Fredman, Ira Tabas
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Brief Report Vascular biology

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

Bishuang Cai, Edward B. Thorp, Amanda C. Doran, Brian E. Sansbury, Mat J.A.P. Daemen, Bernhard Dorweiler, Matthew Spite, Gabrielle Fredman, Ira Tabas

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Figure 3

Suppression of MerTK cleavage improves features of resolution in plaques and increases aortic content of specialized proresolving mediators.

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Suppression of MerTK cleavage improves features of resolution in plaques...
(A) Aortic root sections from WT → Ldlr–/– and MertkCR → Ldlr–/– bone marrow–transplanted mice were stained with Picrosirius red. Quantified data are presented as the ratio of fibrous cap thickness to lesion area, expressed as arbitrary units (AU) (n = 8 per group). *P < 0.05. (B) A subset of aortic root sections was chosen randomly for quantification of Col1a1 mRNA by reverse transcriptase quantitative PCR, with normalization to Gapdh mRNA (n = 6 for each group). *P < 0.05. (C) FoxP3+ Tregs and total CD3+ T cells were quantified in aortic root sections by immunofluorescence microscopy and expressed as percentage Tregs/CD3+ cells (n = 10 for each group). The average absolute numbers of these cells, most of which were in the adventitia, were 8 ± 2.49 and 19 ± 3.74 per section for FoxP3+ Tregs (*P < 0.05) and 106 ± 16.13 and 107 ± 14.33 per section for CD3+ cells (NS) for the WT and MertkCR cohorts, respectively. (D and E) Quantification of specialized proresolving mediators (SPMs) and ratio of aortic 5-LOX–derived SPMs/leukotrienes (LTs) in aorta of WT → Ldlr–/– (n = 8) versus MertkCR → Ldlr–/– (n = 9) bone marrow–transplanted mice. *P < 0.05. (F) Correlation of the ratio of 5-LOX–derived SPMs/leukotrienes with necrotic core area (n = 17). P represents the 2-tailed probability value of a Pearson correlation coefficient. A 2-tailed Student’s t test was used for A–E.