MerTK Expression and ERK Activation Are Essential for the Functional Maturation of Osteopontin‐Producing Reparative Macrophages After Myocardial Infarction
Background We previously reported that osteopontin plays an essential role in accelerating both reparative fibrosis and clearance of dead cells (efferocytosis) during tissue repair after myocardial infarction (MI) and galectin‐3hiCD206+ macrophages is the main source of osteopontin in post‐MI heart....
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-09-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.120.017071 |
| _version_ | 1797229331285540864 |
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| author | Kohsuke Shirakawa Jin Endo Masaharu Kataoka Yoshinori Katsumata Atsushi Anzai Hidenori Moriyama Hiroki Kitakata Takahiro Hiraide Seien Ko Shinichi Goto Genki Ichihara Keiichi Fukuda Tohru Minamino Motoaki Sano |
| author_facet | Kohsuke Shirakawa Jin Endo Masaharu Kataoka Yoshinori Katsumata Atsushi Anzai Hidenori Moriyama Hiroki Kitakata Takahiro Hiraide Seien Ko Shinichi Goto Genki Ichihara Keiichi Fukuda Tohru Minamino Motoaki Sano |
| author_sort | Kohsuke Shirakawa |
| collection | DOAJ |
| description | Background We previously reported that osteopontin plays an essential role in accelerating both reparative fibrosis and clearance of dead cells (efferocytosis) during tissue repair after myocardial infarction (MI) and galectin‐3hiCD206+ macrophages is the main source of osteopontin in post‐MI heart. Interleukin‐10– STAT3 (signal transducer and activator of transcription 3)–galectin‐3 axis is essential for Spp1 (encoding osteopontin) transcriptional activation in cardiac macrophages after MI. Here, we investigated the more detailed mechanism responsible for functional maturation of osteopontin‐producing macrophages. Methods and Results In post‐MI hearts, Spp1 transcriptional activation occurred almost exclusively in MerTK (Mer tyrosine kinase)+ galectin‐3hi macrophages. The induction of MerTK on galectin‐3hi macrophages is essential for their functional maturation including efferocytosis and Spp1 transcriptional activity. MerTK+galectin‐3hi macrophages showed a strong activation of both STAT3 and ERK (extracellular signal‐regulated kinase). STAT3 inhibition suppressed the differentiation of osteopontin‐producing MerTK+galectin‐3hi macrophages, however, STAT3 activation was insufficient at inducing Spp1 transcriptional activity. ERK inhibition suppressed Spp1 transcriptional activation without affecting MerTK or galectin‐3 expression. Concomitant activation of ERK is required for transcriptional activation of Spp1. In Il‐10 knockout enhanced green fluorescent protein–Spp1 knock‐in mice subjected to MI, osteopontin‐producing macrophages decreased but did not disappear entirely. Interleukin‐10 and macrophage colony‐stimulating factor synergistically activated STAT3 and ERK and promoted the differentiation of osteopontin‐producing MerTK+galectin‐3hi macrophages in bone marrow–derived macrophages. Coadministration of anti‐interleukin‐10 plus anti–macrophage colony‐stimulating factor antibodies substantially reduced the number of osteopontin‐producing macrophages by more than anti–interleukin‐10 antibody alone in post‐MI hearts. Conclusions Interleukin‐10 and macrophage colony‐stimulating factor act synergistically to activate STAT3 and ERK in cardiac macrophages, which in turn upregulate the expression of galectin‐3 and MerTK, leading to the functional maturation of osteopontin‐producing macrophages. |
| first_indexed | 2024-04-24T15:10:53Z |
| format | Article |
| id | doaj.art-b31e87ab8ac14b58918885c9998400f3 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-04-24T15:10:53Z |
| publishDate | 2020-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-b31e87ab8ac14b58918885c9998400f32024-04-02T11:31:38ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802020-09-0191810.1161/JAHA.120.017071MerTK Expression and ERK Activation Are Essential for the Functional Maturation of Osteopontin‐Producing Reparative Macrophages After Myocardial InfarctionKohsuke Shirakawa0Jin Endo1Masaharu Kataoka2Yoshinori Katsumata3Atsushi Anzai4Hidenori Moriyama5Hiroki Kitakata6Takahiro Hiraide7Seien Ko8Shinichi Goto9Genki Ichihara10Keiichi Fukuda11Tohru Minamino12Motoaki Sano13Department of Cardiovascular Biology and Medicine Niigata University Graduate School of Medical and Dental Sciences Niigata JapanDepartment of Cardiology Keio University School of Medicine Tokyo JapanDepartment of Cardiology Keio University School of Medicine Tokyo JapanDepartment of Cardiology Keio University School of Medicine Tokyo JapanDepartment of Cardiology Keio University School of Medicine Tokyo JapanDepartment of Cardiology Keio University School of Medicine Tokyo JapanDepartment of Cardiology Keio University School of Medicine Tokyo JapanDepartment of Cardiology Keio University School of Medicine Tokyo JapanDepartment of Cardiology Keio University School of Medicine Tokyo JapanDepartment of Cardiology Keio University School of Medicine Tokyo JapanDepartment of Cardiology Keio University School of Medicine Tokyo JapanDepartment of Cardiology Keio University School of Medicine Tokyo JapanDepartment of Cardiovascular Biology and Medicine Niigata University Graduate School of Medical and Dental Sciences Niigata JapanDepartment of Cardiology Keio University School of Medicine Tokyo JapanBackground We previously reported that osteopontin plays an essential role in accelerating both reparative fibrosis and clearance of dead cells (efferocytosis) during tissue repair after myocardial infarction (MI) and galectin‐3hiCD206+ macrophages is the main source of osteopontin in post‐MI heart. Interleukin‐10– STAT3 (signal transducer and activator of transcription 3)–galectin‐3 axis is essential for Spp1 (encoding osteopontin) transcriptional activation in cardiac macrophages after MI. Here, we investigated the more detailed mechanism responsible for functional maturation of osteopontin‐producing macrophages. Methods and Results In post‐MI hearts, Spp1 transcriptional activation occurred almost exclusively in MerTK (Mer tyrosine kinase)+ galectin‐3hi macrophages. The induction of MerTK on galectin‐3hi macrophages is essential for their functional maturation including efferocytosis and Spp1 transcriptional activity. MerTK+galectin‐3hi macrophages showed a strong activation of both STAT3 and ERK (extracellular signal‐regulated kinase). STAT3 inhibition suppressed the differentiation of osteopontin‐producing MerTK+galectin‐3hi macrophages, however, STAT3 activation was insufficient at inducing Spp1 transcriptional activity. ERK inhibition suppressed Spp1 transcriptional activation without affecting MerTK or galectin‐3 expression. Concomitant activation of ERK is required for transcriptional activation of Spp1. In Il‐10 knockout enhanced green fluorescent protein–Spp1 knock‐in mice subjected to MI, osteopontin‐producing macrophages decreased but did not disappear entirely. Interleukin‐10 and macrophage colony‐stimulating factor synergistically activated STAT3 and ERK and promoted the differentiation of osteopontin‐producing MerTK+galectin‐3hi macrophages in bone marrow–derived macrophages. Coadministration of anti‐interleukin‐10 plus anti–macrophage colony‐stimulating factor antibodies substantially reduced the number of osteopontin‐producing macrophages by more than anti–interleukin‐10 antibody alone in post‐MI hearts. Conclusions Interleukin‐10 and macrophage colony‐stimulating factor act synergistically to activate STAT3 and ERK in cardiac macrophages, which in turn upregulate the expression of galectin‐3 and MerTK, leading to the functional maturation of osteopontin‐producing macrophages.https://www.ahajournals.org/doi/10.1161/JAHA.120.017071galectin‐3macrophagemacrophage colony‐stimulating factorMerTKmyocardial infarctionosteopontin |
| spellingShingle | Kohsuke Shirakawa Jin Endo Masaharu Kataoka Yoshinori Katsumata Atsushi Anzai Hidenori Moriyama Hiroki Kitakata Takahiro Hiraide Seien Ko Shinichi Goto Genki Ichihara Keiichi Fukuda Tohru Minamino Motoaki Sano MerTK Expression and ERK Activation Are Essential for the Functional Maturation of Osteopontin‐Producing Reparative Macrophages After Myocardial Infarction Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease galectin‐3 macrophage macrophage colony‐stimulating factor MerTK myocardial infarction osteopontin |
| title | MerTK Expression and ERK Activation Are Essential for the Functional Maturation of Osteopontin‐Producing Reparative Macrophages After Myocardial Infarction |
| title_full | MerTK Expression and ERK Activation Are Essential for the Functional Maturation of Osteopontin‐Producing Reparative Macrophages After Myocardial Infarction |
| title_fullStr | MerTK Expression and ERK Activation Are Essential for the Functional Maturation of Osteopontin‐Producing Reparative Macrophages After Myocardial Infarction |
| title_full_unstemmed | MerTK Expression and ERK Activation Are Essential for the Functional Maturation of Osteopontin‐Producing Reparative Macrophages After Myocardial Infarction |
| title_short | MerTK Expression and ERK Activation Are Essential for the Functional Maturation of Osteopontin‐Producing Reparative Macrophages After Myocardial Infarction |
| title_sort | mertk expression and erk activation are essential for the functional maturation of osteopontin producing reparative macrophages after myocardial infarction |
| topic | galectin‐3 macrophage macrophage colony‐stimulating factor MerTK myocardial infarction osteopontin |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.120.017071 |
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