The AIM2 inflammasome exacerbates atherosclerosis in clonal haematopoiesis
| Autor: | Eirini P. Papapetrou, Oliver Soehnlein, Andriana G. Kotini, Ying Wei, Ross L. Levine, David G. Thomas, Marit Westerterp, Joachim Pircher, Hans-Willem Snoeck, Steffen Massberg, Alan R. Tall, Larry Luchsinger, Nan Wang, Chenyi Xue, Carlos Silvestre-Roig, Tong Xiao, M. Yalcinkaya, Trevor P. Fidler, Peter Libby, Christian Schulz, Mohammad Ali Hajebrahimi, Brian Hardaway, Wenli Liu, Muredach P. Reilly, Benjamin L. Ebert, Sandra Abramowicz |
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| Přispěvatelé: | Center for Liver, Digestive and Metabolic Diseases (CLDM), Translational Immunology Groningen (TRIGR) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Inflammasomes Interleukin-1beta Caspase 1 030204 cardiovascular system & hematology medicine.disease_cause Antibodies Article 03 medical and health sciences AIM2 Mice 0302 clinical medicine Bone Marrow medicine Pyroptosis Animals Humans RNA-Seq Caspase Inflammation Mutation Multidisciplinary biology Macrophages Intracellular Signaling Peptides and Proteins Inflammasome Janus Kinase 2 Phosphate-Binding Proteins Atherosclerosis Caspases Initiator DNA-Binding Proteins Mice Inbred C57BL Haematopoiesis Disease Models Animal Interleukin 1 Receptor Antagonist Protein 030104 developmental biology biology.protein Cancer research Female Clonal Hematopoiesis Single-Cell Analysis Macrophage proliferation medicine.drug |
| Zdroj: | The journal of cardiovascular aging Nature, 592(7853), 296-301. Nature Publishing Group Nature |
| ISSN: | 0028-0836 |
| DOI: | 10.1038/s41586-021-03341-5 |
| Popis: | Clonal haematopoiesis, which is highly prevalent in older individuals, arises from somatic mutations that endow a proliferative advantage to haematopoietic cells. Clonal haematopoiesis increases the risk of myocardial infarction and stroke independently of traditional risk factors1. Among the common genetic variants that give rise to clonal haematopoiesis, the JAK2V617F (JAK2VF) mutation, which increases JAK–STAT signalling, occurs at a younger age and imparts the strongest risk of premature coronary heart disease1,2. Here we show increased proliferation of macrophages and prominent formation of necrotic cores in atherosclerotic lesions in mice that express Jak2VF selectively in macrophages, and in chimeric mice that model clonal haematopoiesis. Deletion of the essential inflammasome components caspase 1 and 11, or of the pyroptosis executioner gasdermin D, reversed these adverse changes. Jak2VF lesions showed increased expression of AIM2, oxidative DNA damage and DNA replication stress, and Aim2 deficiency reduced atherosclerosis. Single-cell RNA sequencing analysis of Jak2VF lesions revealed a landscape that was enriched for inflammatory myeloid cells, which were suppressed by deletion of Gsdmd. Inhibition of the inflammasome product interleukin-1β reduced macrophage proliferation and necrotic formation while increasing the thickness of fibrous caps, indicating that it stabilized plaques. Our findings suggest that increased proliferation and glycolytic metabolism in Jak2VF macrophages lead to DNA replication stress and activation of the AIM2 inflammasome, thereby aggravating atherosclerosis. Precise application of therapies that target interleukin-1β or specific inflammasomes according to clonal haematopoiesis status could substantially reduce cardiovascular risk. Accelerated atherosclerosis in a mouse model of clonal haematopoiesis is prevented by genetic interruption of AIM2 inflammasome activation or by inhibition of interleukin-1β. |
| Databáze: | OpenAIRE |
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