Title | MerTK Cleavage on Resident Cardiac Macrophages Compromises Repair After Myocardial Ischemia Reperfusion Injury. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | DeBerge M, Yeap XYi, Dehn S, Zhang S, Grigoryeva L, Misener S, Procissi D, Zhou X, Lee DC, Muller WA, Luo X, Rothlin C, Tabas I, Thorp EB |
Journal | Circ Res |
Volume | 121 |
Issue | 8 |
Pagination | 930-940 |
Date Published | 2017 Sep 29 |
ISSN | 1524-4571 |
Keywords | Animals, Apoptosis, c-Mer Tyrosine Kinase, Cytokines, Disease Models, Animal, Female, Genetic Predisposition to Disease, Histocompatibility Antigens Class II, Humans, Immunity, Innate, Macrophages, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Monocytes, Myocardial Reperfusion Injury, Myocardium, Phagocytosis, Phenotype, Proteolysis, Proto-Oncogene Proteins, Receptor Protein-Tyrosine Kinases, Receptors, CCR2, Signal Transduction, ST Elevation Myocardial Infarction, Time Factors |
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 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, ) mice, which are resistant to cleavage, showed significantly reduced infarct sizes and improved systolic function. In contrast to other cardiac phagocyte subsets, resident cardiac MHCIICCR2 (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. deficiency compromised the accumulation of MHCII phagocytes, and this was rescued in ) 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 MHCII cardiac macrophages as a novel contributor and therapeutic target of reperfusion injury. |
DOI | 10.1161/CIRCRESAHA.117.311327 |
Alternate Journal | Circ. Res. |
PubMed ID | 28851810 |
PubMed Central ID | PMC5623080 |
Grant List | R01 HL064774 / HL / NHLBI NIH HHS / United States R01 HL046849 / HL / NHLBI NIH HHS / United States F32 HL127958 / HL / NHLBI NIH HHS / United States R01 HL122309 / HL / NHLBI NIH HHS / United States R01 HL132412 / HL / NHLBI NIH HHS / United States UL1 TR001422 / TR / NCATS NIH HHS / United States R01 HL127464 / HL / NHLBI NIH HHS / United States R01 HL075662 / HL / NHLBI NIH HHS / United States R01 AI089824 / AI / NIAID NIH HHS / United States |
Submitted by kej2006 on June 6, 2018 - 4:12pm