The AIM2 inflammasome exacerbates atherosclerosis in clonal haematopoiesis

Trevor P. Fidler (), Chenyi Xue, Mustafa Yalcinkaya, Brian Hardaway, Sandra Abramowicz, Tong Xiao, Wenli Liu, David G. Thomas, Mohammad Ali Hajebrahimi, Joachim Pircher, Carlos Silvestre-Roig, Andriana G. Kotini, Larry L. Luchsinger, Ying Wei, Marit Westerterp, Hans-Willem Snoeck, Eirini P. Papapetrou, Christian Schulz, Steffen Massberg, Oliver Soehnlein, Benjamin Ebert, Ross L. Levine, Muredach P. Reilly, Peter Libby, Nan Wang () and Alan R. Tall ()
Additional contact information
Trevor P. Fidler: Columbia University Irving Medical Center
Chenyi Xue: Columbia University Irving Medical Center
Mustafa Yalcinkaya: Columbia University Irving Medical Center
Brian Hardaway: Columbia University Irving Medical Center
Sandra Abramowicz: Columbia University Irving Medical Center
Tong Xiao: Columbia University Irving Medical Center
Wenli Liu: Columbia University Irving Medical Center
David G. Thomas: Columbia University Irving Medical Center
Mohammad Ali Hajebrahimi: Ludwig Maximilian University
Joachim Pircher: Ludwig Maximilian University
Carlos Silvestre-Roig: Partner Site Munich Heart Alliance
Andriana G. Kotini: Icahn School of Medicine at Mount Sinai
Larry L. Luchsinger: Columbia University Irving Medical Center
Ying Wei: Columbia University
Marit Westerterp: Columbia University Irving Medical Center
Hans-Willem Snoeck: Columbia University Irving Medical Center
Eirini P. Papapetrou: Icahn School of Medicine at Mount Sinai
Christian Schulz: Ludwig Maximilian University
Steffen Massberg: Ludwig Maximilian University
Oliver Soehnlein: Partner Site Munich Heart Alliance
Benjamin Ebert: Dana-Faber Cancer Institute
Ross L. Levine: Memorial Sloan Kettering Cancer Center
Muredach P. Reilly: Columbia University Irving Medical Center
Peter Libby: Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School
Nan Wang: Columbia University Irving Medical Center
Alan R. Tall: Columbia University Irving Medical Center

Nature, 2021, vol. 592, issue 7853, 296-301

Abstract: 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 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.

Date: 2021
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DOI: 10.1038/s41586-021-03341-5

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