Interleukin-1β suppression dampens inflammatory leucocyte production and uptake in atherosclerosis.

Autor:	Hettwer J; Department of Cardiology, German Heart Centre Munich, Technical University Munich, Lazarettstr. 36, 80636 Munich, Germany.; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany., Hinterdobler J; Department of Cardiology, German Heart Centre Munich, Technical University Munich, Lazarettstr. 36, 80636 Munich, Germany.; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany., Miritsch B; Department of Cardiology, German Heart Centre Munich, Technical University Munich, Lazarettstr. 36, 80636 Munich, Germany.; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany., Deutsch MA; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.; Department of Cardiac Surgery, German Heart Centre Munich, Technical University Munich, Munich, Germany., Li X; Department of Cardiac Surgery, German Heart Centre Munich, Technical University Munich, Munich, Germany., Mauersberger C; Department of Cardiology, German Heart Centre Munich, Technical University Munich, Lazarettstr. 36, 80636 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, Lazarettstr. 36, 80636 Munich, Germany.; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany., Braster Q; Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian University of Munich, Munich, Germany., Gram H; Novartis Institutes of BioMedical Research, Basel, Switzerland., Robertson AAB; School of Chemistry and Molecular Biosciences, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, Australia., Cooper MA; School of Chemistry and Molecular Biosciences, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, Australia., Groß O; Institute of Neuropathology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany., Krane M; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.; Department of Cardiac Surgery, German Heart Centre Munich, Technical University Munich, Munich, Germany., Weber C; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.; Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian University of Munich, Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands., Koenig W; Department of Cardiology, German Heart Centre Munich, Technical University Munich, Lazarettstr. 36, 80636 Munich, Germany.; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany., Soehnlein O; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.; Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian University of Munich, Munich, Germany.; Department of Physiology and Pharmacology (FyFa), Karolinska Institute, Stockholm, Sweden., Adamstein NH; Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Ridker P; Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Schunkert H; Department of Cardiology, German Heart Centre Munich, Technical University Munich, Lazarettstr. 36, 80636 Munich, Germany.; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany., Libby P; Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Kessler T; Department of Cardiology, German Heart Centre Munich, Technical University Munich, Lazarettstr. 36, 80636 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, Lazarettstr. 36, 80636 Munich, Germany.; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2022 Oct 21; Vol. 118 (13), pp. 2778-2791.
DOI:	10.1093/cvr/cvab337
Abstrakt:	Aims: Targeting vascular inflammation represents a novel therapeutic approach to reduce complications of atherosclerosis. Neutralizing the pro-inflammatory cytokine interleukin-1β (IL-1β) using canakinumab, a monoclonal antibody, reduces the incidence of cardiovascular events in patients after myocardial infarction (MI). The biological basis for these beneficial effects remains incompletely understood. We sought to explore the mechanisms of IL-1β-targeted therapies. Methods and Results: In mice with early atherosclerosis (ApoE-/- mice on a high-cholesterol diet for 6 weeks), we found that 3 weeks of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3)-inflammasome inhibition or anti-IL-1β treatment (using either MCC950, an NLRP3-inflammasome inhibitor which blocks production and release of active IL-1β, or a murine analogue of canakinumab) dampened accumulation of leucocytes in atherosclerotic aortas, which consequently resulted in slower progression of atherosclerosis. Causally, we found that endothelial cells from atherosclerotic aortas lowered expression of leucocyte chemoattractants and adhesion molecules upon NLRP3-inflammasome inhibition, indicating that NLRP3-inflammasome- and IL-1β-targeted therapies reduced blood leucocyte recruitment to atherosclerotic aortas. In accord, adoptive transfer experiments revealed that anti-IL-1β treatment mitigated blood myeloid cell uptake to atherosclerotic aortas. We further report that anti-IL-1β treatment and NLRP3-inflammasome inhibition reduced inflammatory leucocyte supply by decreasing proliferation of bone marrow haematopoietic stem and progenitor cells, demonstrating that suppression of IL-1β and the NLRP3-inflammasome lowered production of disease-propagating leucocytes. Using bone marrow reconstitution experiments, we observed that haematopoietic cell-specific NLRP3-inflammasome activity contributed to both enhanced recruitment and increased supply of blood inflammatory leucocytes. Further experiments that queried whether anti-IL-1β treatment reduced vascular inflammation also in post-MI accelerated atherosclerosis documented the operation of convergent mechanisms (reduced supply and uptake of inflammatory leucocytes). In line with our pre-clinical findings, post-MI patients on canakinumab treatment showed reduced blood monocyte numbers. Conclusions: Our murine and human data reveal that anti-IL-1β treatment and NLRP3-inflammasome inhibition dampened vascular inflammation and progression of atherosclerosis through reduced blood inflammatory leucocyte (i) supply and (ii) uptake into atherosclerotic aortas providing additional mechanistic insights into links between haematopoiesis and atherogenesis, and into the beneficial effects of NLRP3-inflammasome- and IL-1β-targeted therapies. Competing Interests: Conflict of interest: H.G. is a full time Novartis employee. H.S. reports personal fees from MSD Sharp & Dohme, AMGEN, Bayer Vital GmbH, Boehringer Ingelheim, Daiichi-Sankyo, Novartis, Servier, Brahms, Bristol-Myers Squibb, Medtronic, Sanofi Aventis, Synlab, Pfizer, grants and personal fees from Astra-Zeneca, and personal fees from Vifor outside the submitted work. H.S. and T.K. are named inventors on a patent application for prevention of restenosis after angioplasty and stent implantation outside the submitted work. T.K. received lecture fees from Bayer AG, Pharmaceuticals. H.B.S. 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. A.A.B.R. is inventor on several licensed patents on novel NLRP3 inhibitors. P.L. is an unpaid consultant to, or involved in, clinical trials for Amgen, AstraZeneca, Esperion Therapeutics, Ionis Pharmaceuticals, Kowa Pharmaceuticals, Novartis, Pfizer, Sanofi-Regeneron, and XBiotech, Inc. He is a member of the scientific advisory boards for Amgen, Corvidia Therapeutics, DalCor Pharmaceuticals, IFM Therapeutics, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, and XBiotech, Inc and also serves on the Board of XBiotech, Inc. P.L.’s laboratory has received research funding in the last 2 years from Novartis, and he has a financial interest in Xbiotech, a company developing therapeutic human antibodies. P.L.’s interests were reviewed and are managed by Brigham and Women’s Hospital and Partners HealthCare, Boston, USA, in accordance with their conflict of interest policies. W.K. reports personal fees from AstraZeneca, Novartis, Pfizer, The Medicines Company, DalCor, Kowa, Amgen, Corvidia, Daiichi-Sankyo, Berlin-Chemie, Sanofi, Bristol-Myers Squibb, and grants and non-financial support from Singulex, Abbott, Roche Diagnostics, and Beckmann, all outside the submitted work. P.R. has received research grant support from Novartis, Kowa, Amarin, Pfizer, and the NHLBI; and has served as a consultant to Corvidia, Novartis, Flame, Agepha, Inflazome, AstraZeneca, Janssen, Civi Biopharm, SOCAR, Novo Nordisk, Uptton, Omeicos, Health Outlook, and Boehringer-Ingelheim. All other authors have nothing to disclose. (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)
Databáze:	MEDLINE
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