Colchicine Impacts Leukocyte Trafficking in Atherosclerosis and Reduces Vascular Inflammation.

Autor:	Meyer-Lindemann U; Department of Cardiology, German Heart Centre Munich, Technical University Munich, Munich, Germany.; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany., Mauersberger C; Department of Cardiology, German Heart Centre Munich, Technical University Munich, Munich, Germany.; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany., Schmidt AC; Department of Cardiology, German Heart Centre Munich, Technical University Munich, Munich, Germany.; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany., Moggio A; Department of Cardiology, German Heart Centre Munich, Technical University Munich, Munich, Germany., Hinterdobler J; Department of Cardiology, German Heart Centre Munich, Technical University Munich, Munich, Germany.; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany., Li X; Department of Cardiology, German Heart Centre Munich, Technical University Munich, Munich, Germany., Khangholi D; Department of Cardiology, German Heart Centre Munich, Technical University Munich, Munich, Germany.; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany., Hettwer J; Department of Cardiology, German Heart Centre Munich, Technical University Munich, Munich, Germany.; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany., Gräßer C; Department of Cardiology, German Heart Centre Munich, Technical University Munich, Munich, Germany.; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany., Dutsch A; Department of Cardiology, German Heart Centre Munich, Technical University Munich, Munich, Germany.; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany., Schunkert H; Department of Cardiology, German Heart Centre Munich, Technical University Munich, Munich, Germany.; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany., Kessler T; Department of Cardiology, German Heart Centre Munich, Technical University Munich, Munich, Germany.; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany., Sager HB; Department of Cardiology, German Heart Centre Munich, Technical University Munich, Munich, Germany.; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2022 Jul 04; Vol. 13, pp. 898690. Date of Electronic Publication: 2022 Jul 04 (Print Publication: 2022).
DOI:	10.3389/fimmu.2022.898690
Abstrakt:	Background: Inflammation strongly contributes to atherosclerosis initiation and progression. Consequently, recent clinical trials pharmacologically targeted vascular inflammation to decrease the incidence of atherosclerosis-related complications. Colchicine, a microtubule inhibitor with anti-inflammatory properties, reduced cardiovascular events in patients with recent acute coronary syndrome and chronic coronary disease. However, the biological basis of these observations remains elusive. We sought to explore the mechanism by which colchicine beneficially alters the course of atherosclerosis. Methods and Results: In mice with early atherosclerosis ( Apoe -/- mice on a high cholesterol diet for 8 weeks), we found that colchicine treatment (0.25 mg/kg bodyweight once daily over four weeks) reduced numbers of neutrophils, inflammatory monocytes and macrophages inside atherosclerotic aortas using flow cytometry and immunohistochemistry. Consequently, colchicine treatment resulted in a less inflammatory plaque composition and reduced plaque size. We next investigated how colchicine prevented plaque leukocyte expansion and found that colchicine treatment mitigated recruitment of blood neutrophils and inflammatory monocytes to plaques as revealed by adoptive transfer experiments. Causally, we found that colchicine reduced levels of both leukocyte adhesion molecules and receptors for leukocyte chemoattractants on blood neutrophils and monocytes. Further experiments showed that colchicine treatment reduced vascular inflammation also in post-myocardial infarction accelerated atherosclerosis through similar mechanisms as documented in early atherosclerosis. When we examined whether colchicine also decreased numbers of macrophages inside atherosclerotic plaques by impacting monocyte/macrophage transitioning or in-situ proliferation of macrophages, we report that colchicine treatment did not influence macrophage precursor differentiation or macrophage proliferation using cell culture experiments with bone marrow derived macrophages. Conclusions: Our data reveal that colchicine prevents expansion of plaque inflammatory leukocytes through lowering recruitment of blood myeloid cells to plaques. These data provide novel mechanistic clues on the beneficial effects of colchicine in the treatment of atherosclerosis and may inform future anti-inflammatory interventions in patients at risk. Competing Interests: HSa reports grants from the European Research Council, the “Else-Kröner-Fresenius-Stiftung”, the “Deutsche Herzstiftung” and the “Deutsche Forschungsgemeinschaft” during the conduct of the study. HSa received lecture fees from Novo Nordisk. HSc reports personal fees from MSD Sharp & Dohme, personal fees from AMGEN, personal fees from Bayer Vital GmbH, personal fees from Boehringer Ingelheim, personal fees from Daiichi-Sankyo, personal fees from Novartis, personal fees from Servier, personal fees from Brahms, personal fees from Bristol-Myers Squibb, personal fees from Medtronic, personal fees from Sanofi Aventis, personal fees from Synlab, personal fees from Pfizer, grants and personal fees from Astra-Zeneca and personal fees from Vifor, outside the submitted work. HSc and TK are named inventors on a patent application for prevention of restenosis after angioplasty and stent implantation outside the submitted work. TK received lecture fees from Bayer AG, Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Meyer-Lindemann, Mauersberger, Schmidt, Moggio, Hinterdobler, Li, Khangholi, Hettwer, Gräßer, Dutsch, Schunkert, Kessler and Sager.)
Databáze:	MEDLINE
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