MerTK cleavage on resident cardiac macrophages compromises repair after myocardial ischemia reperfusion injury

Matthew DeBerge, Xin Yi Yeap, Shirley Dehn, Shuang Zhang, Lubov Grigoryeva, Sol Misener, Daniel Procissi, Xin Zhou, Daniel C. Lee, William A. Muller, Xunrong Luo, Carla Rothlin, Ira Tabas, Edward B. Thorp*

*Corresponding author for this work

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)930-940
Number of pages11
JournalCirculation research
Volume121
Issue number8
DOIs
StatePublished - Sep 1 2017

Fingerprint

Myocardial Reperfusion Injury
Reperfusion Injury
Myocardial Ischemia
Phagocytes
Macrophages
Reperfusion
Myocardial Reperfusion
Monocytes
CCR Receptors
Myocardial Infarction
Transforming Growth Factors
Debridement
Major Histocompatibility Complex
Phagocytosis
Protein-Tyrosine Kinases
Ischemia
Biomarkers
Cytokines
Wounds and Injuries
Therapeutics

Keywords

  • Efferocytosis
  • Inflammation
  • Ischemia reperfusion injury
  • Macrophage
  • Phagocytosis

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

DeBerge, Matthew ; Yeap, Xin Yi ; Dehn, Shirley ; Zhang, Shuang ; Grigoryeva, Lubov ; Misener, Sol ; Procissi, Daniel ; Zhou, Xin ; Lee, Daniel C. ; Muller, William A. ; Luo, Xunrong ; Rothlin, Carla ; Tabas, Ira ; Thorp, Edward B. / MerTK cleavage on resident cardiac macrophages compromises repair after myocardial ischemia reperfusion injury. In: Circulation research. 2017 ; Vol. 121, No. 8. pp. 930-940.
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abstract = "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.",
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MerTK cleavage on resident cardiac macrophages compromises repair after myocardial ischemia reperfusion injury. / DeBerge, Matthew; Yeap, Xin Yi; Dehn, Shirley; Zhang, Shuang; Grigoryeva, Lubov; Misener, Sol; Procissi, Daniel; Zhou, Xin; Lee, Daniel C.; Muller, William A.; Luo, Xunrong; Rothlin, Carla; Tabas, Ira; Thorp, Edward B.

In: Circulation research, Vol. 121, No. 8, 01.09.2017, p. 930-940.

Research output: Contribution to journalArticle

TY - JOUR

T1 - MerTK cleavage on resident cardiac macrophages compromises repair after myocardial ischemia reperfusion injury

AU - DeBerge, Matthew

AU - Yeap, Xin Yi

AU - Dehn, Shirley

AU - Zhang, Shuang

AU - Grigoryeva, Lubov

AU - Misener, Sol

AU - Procissi, Daniel

AU - Zhou, Xin

AU - Lee, Daniel C.

AU - Muller, William A.

AU - Luo, Xunrong

AU - Rothlin, Carla

AU - Tabas, Ira

AU - Thorp, Edward B.

PY - 2017/9/1

Y1 - 2017/9/1

N2 - 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.

AB - 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.

KW - Efferocytosis

KW - Inflammation

KW - Ischemia reperfusion injury

KW - Macrophage

KW - Phagocytosis

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