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MST1\/2 (mammalian STE20-like protein kinase 1\/2) acts as a regulator of macrophage-associated immune responses to bacterial infections. However, the role of MST1\/2 in regulating macrophage phenotype and function in myocardial infarction (MI) remains unclear.<\/jats:p>\n <\/jats:sec>\n \n Objective:<\/jats:title>\n To determine the function and underlying mechanism of macrophage MST1\/2 in cardiac repair post-MI.<\/jats:p>\n <\/jats:sec>\n \n Methods and Results:<\/jats:title>\n \n Using\n LysMCre<\/jats:italic>\n -mediated\n Mst1\/2<\/jats:italic>\n -deficient mice, we found that MST1 deficiency exacerbated cardiac dysfunction after MI. Single-cell RNA sequencing assay indicated that the effect was attributed to a shift of macrophage subtypes from those expressing\n Cxcl2<\/jats:italic>\n and\n Cd163<\/jats:italic>\n toward\n Ccl2<\/jats:italic>\n and\n Ccl4<\/jats:italic>\n expression. Mass spectrometry identified LTB4 (leukotriene B4) as the lipid mediator that was upregulated in the absence of MST1. We found that MST1 phosphorylated 5-LOX (5-lipoxygenase) at its T218 residue, disrupting the interaction between 5-LOX and 5-LOX-activating protein, resulting in a reduction of LTB4 production. In contrast, a 5-LOX\n T218A<\/jats:sup>\n variant showed no response to MST1. Moreover, treatment of peritoneal macrophages with LTB4 or medium conditioned by\n Mst1<\/jats:italic>\n -deficient macrophages resulted in high\n Ccl2<\/jats:italic>\n and\n Ccl4<\/jats:italic>\n expression and low\n Cxcl2<\/jats:italic>\n and\n Cd163<\/jats:italic>\n expression, except when the cells were co-treated with the BLT1 (LTB4 receptor 1) antagonist CP105696. Furthermore, CP105696 ameliorated cardiac dysfunction in\n LysMCre<\/jats:italic>\n -mediated\n Mst1\/2<\/jats:italic>\n -deficient mice and enhanced cardiac repair in wild-type mice treated with XMU-MP-1 (4-((5,10-dimethyl-6-oxo-6,10-dihydro-5H-pyrimido[5,4-b]thieno[3,2-e][1,4]diazepin-2-yl)amino)benzenesulfonamide) after MI.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions:<\/jats:title>\n Taken together, our results demonstrate that inhibition of MST1\/2 impaired post-MI repair through activating macrophage 5-LOX\u2013LTB4\u2013BLT1 axis.<\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/circresaha.121.319687","type":"journal-article","created":{"date-parts":[[2021,9,13]],"date-time":"2021-09-13T15:51:22Z","timestamp":1631548282000},"page":"909-926","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":36,"title":["Macrophage MST1\/2 Disruption Impairs Post-Infarction Cardiac Repair via LTB4"],"prefix":"10.1161","volume":"129","author":[{"given":"Mingming","family":"Liu","sequence":"first","affiliation":[{"name":"Tianjin Key Laboratory of Ion and Molecular Function of Cardiovascular Diseases, Tianjin Institute of Cardiology, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), the Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics (M.L., M.Y., H.L., D.A.), Tianjin Medical University."},{"name":"Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital (M.L.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7421-578X","authenticated-orcid":true,"given":"Meng","family":"Yan","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory of Ion and Molecular Function of Cardiovascular Diseases, Tianjin Institute of Cardiology, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), the Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics (M.L., M.Y., H.L., D.A.), Tianjin Medical University."},{"name":"The First Affiliated Hospital of Soochow University Department of Pathology, Soochow University, Suzhou (M.Y.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinlong","family":"He","sequence":"additional","affiliation":[{"name":"Physiology and Pathophysiology (J.H., H.L., Z.C., W.C., X.Z., Y.Z., D.A.), Tianjin Medical University."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huizhen","family":"Lv","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory of Ion and Molecular Function of Cardiovascular Diseases, Tianjin Institute of Cardiology, State Key Laboratory of Experimental 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