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MerTK Cleavage on Resident Cardiac Macrophages Compromises Repair After Myocardial Ischemia Reperfusion Injury.

Publication ,  Journal Article
DeBerge, M; Yeap, XY; Dehn, S; Zhang, S; Grigoryeva, L; Misener, S; Procissi, D; Zhou, X; Lee, DC; Muller, WA; Luo, X; Rothlin, C; Tabas, I; Thorp, EB
Published in: Circ Res
September 29, 2017

RATIONALE: Clinical benefits of reperfusion after myocardial infarction are offset by maladaptive innate immune cell function, and therapeutic interventions are lacking. OBJECTIVE: We sought to test the significance of phagocytic clearance by resident and recruited phagocytes after myocardial ischemia reperfusion. METHODS AND RESULTS: In humans, we discovered that clinical reperfusion after myocardial infarction led to significant elevation of the soluble form of MerTK (myeloid-epithelial-reproductive tyrosine kinase; ie, soluble MER), a critical biomarker of compromised phagocytosis by innate macrophages. In reperfused mice, macrophage Mertk deficiency led to decreased cardiac wound debridement, increased infarct size, and depressed cardiac function, newly implicating MerTK in cardiac repair after myocardial ischemia reperfusion. More notably, Mertk(CR) mice, which are resistant to cleavage, showed significantly reduced infarct sizes and improved systolic function. In contrast to other cardiac phagocyte subsets, resident cardiac MHCIILOCCR2- (major histocompatibility complex II/C-C motif chemokine receptor type 2) macrophages expressed higher levels of MerTK and, when exposed to apoptotic cells, secreted proreparative cytokines, including transforming growth factor-β. Mertk deficiency compromised the accumulation of MHCIILO phagocytes, and this was rescued in Mertk(CR) mice. Interestingly, blockade of CCR2-dependent monocyte infiltration into the heart reduced soluble MER levels post-ischemia reperfusion. CONCLUSIONS: Our data implicate monocyte-induced MerTK cleavage on proreparative MHCIILO cardiac macrophages as a novel contributor and therapeutic target of reperfusion injury.

Duke Scholars

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Published In

Circ Res

DOI

EISSN

1524-4571

Publication Date

September 29, 2017

Volume

121

Issue

8

Start / End Page

930 / 940

Location

United States

Related Subject Headings

  • c-Mer Tyrosine Kinase
  • Time Factors
  • Signal Transduction
  • ST Elevation Myocardial Infarction
  • Receptors, CCR2
  • Receptor Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins
  • Proteolysis
  • Phenotype
  • Phagocytosis
 

Citation

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DeBerge, M., Yeap, X. Y., Dehn, S., Zhang, S., Grigoryeva, L., Misener, S., … Thorp, E. B. (2017). MerTK Cleavage on Resident Cardiac Macrophages Compromises Repair After Myocardial Ischemia Reperfusion Injury. Circ Res, 121(8), 930–940. https://doi.org/10.1161/CIRCRESAHA.117.311327
DeBerge, Matthew, Xin Yi Yeap, Shirley Dehn, Shuang Zhang, Lubov Grigoryeva, Sol Misener, Daniel Procissi, et al. “MerTK Cleavage on Resident Cardiac Macrophages Compromises Repair After Myocardial Ischemia Reperfusion Injury.Circ Res 121, no. 8 (September 29, 2017): 930–40. https://doi.org/10.1161/CIRCRESAHA.117.311327.
DeBerge M, Yeap XY, Dehn S, Zhang S, Grigoryeva L, Misener S, et al. MerTK Cleavage on Resident Cardiac Macrophages Compromises Repair After Myocardial Ischemia Reperfusion Injury. Circ Res. 2017 Sep 29;121(8):930–40.
DeBerge, Matthew, et al. “MerTK Cleavage on Resident Cardiac Macrophages Compromises Repair After Myocardial Ischemia Reperfusion Injury.Circ Res, vol. 121, no. 8, Sept. 2017, pp. 930–40. Pubmed, doi:10.1161/CIRCRESAHA.117.311327.
DeBerge M, Yeap XY, Dehn S, Zhang S, Grigoryeva L, Misener S, Procissi D, Zhou X, Lee DC, Muller WA, Luo X, Rothlin C, Tabas I, Thorp EB. MerTK Cleavage on Resident Cardiac Macrophages Compromises Repair After Myocardial Ischemia Reperfusion Injury. Circ Res. 2017 Sep 29;121(8):930–940.

Published In

Circ Res

DOI

EISSN

1524-4571

Publication Date

September 29, 2017

Volume

121

Issue

8

Start / End Page

930 / 940

Location

United States

Related Subject Headings

  • c-Mer Tyrosine Kinase
  • Time Factors
  • Signal Transduction
  • ST Elevation Myocardial Infarction
  • Receptors, CCR2
  • Receptor Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins
  • Proteolysis
  • Phenotype
  • Phagocytosis