The AIM2 inflammasome exacerbates atherosclerosis in clonal haematopoiesis

Fidler, Trevor P.; Xue, Chenyi; Yalcinkaya, Mustafa; Hardaway, Brian; Abramowicz, Sandra; Xiao, Tong; Liu, Wenli; Thomas, David G.; Hajebrahimi, Mohammad Ali; Pircher, Joachim; Silvestre-Roig, Carlos; Kotini, Andriana G.; Luchsinger, Larry L.; Wei, Ying; Westerterp, Marit; Snoeck, Hans-Willem; Papapetrou, Eirini P.; Schulz, Christian; Massberg, Steffen; Soehnlein, Oliver; Ebert, Benjamin; Levine, Ross L.; Reilly, Muredach P.; Libby, Peter; Wang, Nan und Tall, Alan R. (2021): The AIM2 inflammasome exacerbates atherosclerosis in clonal haematopoiesis. In: Nature, Bd. 592, Nr. 7853: S. 296-301

Abstract

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 factors(1). Among the common genetic variants that give rise to clonal haematopoiesis, the JAK2(V617F) (JAK2(VF)) mutation, which increases JAK-STAT signalling, occurs at a younger age and imparts the strongest risk of premature coronary heart disease(1,2). Here we show increased proliferation of macrophages and prominent formation of necrotic cores in atherosclerotic lesions in mice that express Jak2(VF) 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. Jak2(VF) lesions showed increased expression of AIM2, oxidative DNA damage and DNA replication stress, and Aim2 deficiency reduced atherosclerosis. Single-cell RNA sequencing analysis of Jak2(VF) lesions revealed a landscape that was enriched for inflammatory myeloid cells, which were suppressed by deletion of Gsdmd. Inhibition of the inflammasome product interleukin-1 beta 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 Jak2(VF) macrophages lead to DNA replication stress and activation of the AIM2 inflammasome, thereby aggravating atherosclerosis. Precise application of therapies that target interleukin-1 beta or specific inflammasomes according to clonal haematopoiesis status could substantially reduce cardiovascular risk.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0028-0836
• Sprache: Englisch