PMID- 30696265 OWN - NLM STAT- MEDLINE DCOM- 20200129 LR - 20200309 IS - 1524-4539 (Electronic) IS - 0009-7322 (Print) IS - 0009-7322 (Linking) VI - 139 IP - 15 DP - 2019 Apr 9 TI - C-X-C Motif Chemokine Receptor 4 Blockade Promotes Tissue Repair After Myocardial Infarction by Enhancing Regulatory T Cell Mobilization and Immune-Regulatory Function. PG - 1798-1812 LID - 10.1161/CIRCULATIONAHA.118.036053 [doi] AB - BACKGROUND: Acute myocardial infarction (MI) elicits an inflammatory response that drives tissue repair and adverse cardiac remodeling. Inflammatory cell trafficking after MI is controlled by C-X-C motif chemokine ligand 12 (CXCL12) and its receptor, C-X-C motif chemokine receptor 4 (CXCR4). CXCR4 antagonists mobilize inflammatory cells and promote infarct repair, but the cellular mechanisms are unclear. METHODS: We investigated the therapeutic potential and mode of action of the peptidic macrocycle CXCR4 antagonist POL5551 in mice with reperfused MI. We applied cell depletion and adoptive transfer strategies using lymphocyte-deficient Rag1 knockout mice; DEREG mice, which express a diphtheria toxin receptor-enhanced green fluorescent protein fusion protein under the control of the promoter/enhancer region of the regulatory T (T(reg)) cell-restricted Foxp3 transcription factor; and dendritic cell-depleted CD11c-Cre iDTR mice. Translational potential was explored in a porcine model of reperfused MI using serial contrast-enhanced magnetic resonance imaging. RESULTS: Intraperitoneal POL5551 injections in wild-type mice (8 mg/kg at 2, 4, 6, and 8 days) enhanced angiogenesis in the infarct border zone, reduced scar size, and attenuated left ventricular remodeling and contractile dysfunction at 28 days. Treatment effects were absent in splenectomized wild-type mice, Rag1 knockout mice, and T(reg) cell-depleted DEREG mice. Conversely, treatment effects could be transferred into infarcted splenectomized wild-type mice by transplanting splenic T(reg) cells from POL5551-treated infarcted DEREG mice. Instructive cues provided by infarct-primed dendritic cells were required for POL5551 treatment effects. POL5551 injections mobilized T(reg) cells into the peripheral blood, followed by enhanced T(reg) cell accumulation in the infarcted region. Neutrophils, monocytes, and lymphocytes displayed similar mobilization kinetics, but their cardiac recruitment was not affected. POL5551, however, attenuated inflammatory gene expression in monocytes and macrophages in the infarcted region via T(reg) cells. Intravenous infusion of the clinical-stage POL5551 analogue POL6326 (3 mg/kg at 4, 6, 8, and 10 days) decreased infarct volume and improved left ventricular ejection fraction in pigs. CONCLUSIONS: These data confirm CXCR4 blockade as a promising treatment strategy after MI. We identify dendritic cell-primed splenic T(reg) cells as the central arbiters of these therapeutic effects and thereby delineate a pharmacological strategy to promote infarct repair by augmenting T(reg) cell function in vivo. FAU - Wang, Yong AU - Wang Y AD - Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology (Y.W., M.K.-K., H.F., E.B., A.K., K.C.W.), Hannover Medical School, Germany. AD - Department of Cardiology and Angiology (Y.W., M.K.-K., L.C.N., H.F., E.B., A.K., J.B., K.C.W.), Hannover Medical School, Germany. FAU - Dembowsky, Klaus AU - Dembowsky K AD - Polyphor Ltd, Allschwil, Switzerland (K.D., E.C.). FAU - Chevalier, Eric AU - Chevalier E AD - Polyphor Ltd, Allschwil, Switzerland (K.D., E.C.). FAU - Stuve, Philipp AU - Stuve P AD - Institute of Infection Immunology, TWINCORE, Hannover, Germany (P.S., M.L., T.S.). AD - The current affiliation for P.S. and T.S. is Department of Medical Microbiology and Hygiene, University Medical Center of the Johannes Gutenberg University Mainz, Germany. FAU - Korf-Klingebiel, Mortimer AU - Korf-Klingebiel M AD - Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology (Y.W., M.K.-K., H.F., E.B., A.K., K.C.W.), Hannover Medical School, Germany. AD - Department of Cardiology and Angiology (Y.W., M.K.-K., L.C.N., H.F., E.B., A.K., J.B., K.C.W.), Hannover Medical School, Germany. FAU - Lochner, Matthias AU - Lochner M AD - Institute of Infection Immunology, TWINCORE, Hannover, Germany (P.S., M.L., T.S.). FAU - Napp, L Christian AU - Napp LC AD - Department of Cardiology and Angiology (Y.W., M.K.-K., L.C.N., H.F., E.B., A.K., J.B., K.C.W.), Hannover Medical School, Germany. FAU - Frank, Heike AU - Frank H AD - Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology (Y.W., M.K.-K., H.F., E.B., A.K., K.C.W.), Hannover Medical School, Germany. AD - Department of Cardiology and Angiology (Y.W., M.K.-K., L.C.N., H.F., E.B., A.K., J.B., K.C.W.), Hannover Medical School, Germany. FAU - Brinkmann, Eva AU - Brinkmann E AD - Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology (Y.W., M.K.-K., H.F., E.B., A.K., K.C.W.), Hannover Medical School, Germany. AD - Department of Cardiology and Angiology (Y.W., M.K.-K., L.C.N., H.F., E.B., A.K., J.B., K.C.W.), Hannover Medical School, Germany. FAU - Kanwischer, Anna AU - Kanwischer A AD - Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology (Y.W., M.K.-K., H.F., E.B., A.K., K.C.W.), Hannover Medical School, Germany. AD - Department of Cardiology and Angiology (Y.W., M.K.-K., L.C.N., H.F., E.B., A.K., J.B., K.C.W.), Hannover Medical School, Germany. FAU - Bauersachs, Johann AU - Bauersachs J AD - Department of Cardiology and Angiology (Y.W., M.K.-K., L.C.N., H.F., E.B., A.K., J.B., K.C.W.), Hannover Medical School, Germany. FAU - Gyongyosi, Mariann AU - Gyongyosi M AD - Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Austria (M.G.). FAU - Sparwasser, Tim AU - Sparwasser T AD - Institute of Infection Immunology, TWINCORE, Hannover, Germany (P.S., M.L., T.S.). AD - The current affiliation for P.S. and T.S. is Department of Medical Microbiology and Hygiene, University Medical Center of the Johannes Gutenberg University Mainz, Germany. FAU - Wollert, Kai C AU - Wollert KC AD - Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology (Y.W., M.K.-K., H.F., E.B., A.K., K.C.W.), Hannover Medical School, Germany. AD - Department of Cardiology and Angiology (Y.W., M.K.-K., L.C.N., H.F., E.B., A.K., J.B., K.C.W.), Hannover Medical School, Germany. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Circulation JT - Circulation JID - 0147763 RN - 0 (Anti-Inflammatory Agents) RN - 0 (CXCR4 protein, mouse) RN - 0 (POL5551) RN - 0 (Proteins) RN - 0 (Receptors, CXCR4) SB - IM CIN - Nat Rev Cardiol. 2019 Apr;16(4):200. PMID: 30728471 MH - Animals MH - Anti-Inflammatory Agents/*pharmacology MH - Dendritic Cells/drug effects/immunology/metabolism MH - Disease Models, Animal MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Myocardial Contraction/drug effects MH - Myocardial Infarction/*drug therapy/immunology/metabolism/pathology MH - Myocardium/immunology/*metabolism/pathology MH - Neovascularization, Physiologic/drug effects MH - Proteins/*pharmacology MH - Receptors, CXCR4/*antagonists & inhibitors/metabolism MH - Recovery of Function MH - Signal Transduction MH - Sus scrofa MH - T-Lymphocytes, Regulatory/*drug effects/immunology/metabolism MH - Ventricular Function, Left/drug effects MH - Ventricular Remodeling/drug effects PMC - PMC6467561 OTO - NOTNLM OT - T cells OT - acute myocardial infarction OT - dendritic cells OT - inflammation OT - receptors, CXCR4 OT - regulatory EDAT- 2019/01/31 06:00 MHDA- 2020/01/30 06:00 PMCR- 2019/04/16 CRDT- 2019/01/31 06:00 PHST- 2019/01/31 06:00 [pubmed] PHST- 2020/01/30 06:00 [medline] PHST- 2019/01/31 06:00 [entrez] PHST- 2019/04/16 00:00 [pmc-release] AID - 10.1161/CIRCULATIONAHA.118.036053 [doi] PST - ppublish SO - Circulation. 2019 Apr 9;139(15):1798-1812. doi: 10.1161/CIRCULATIONAHA.118.036053.