Author + information
- Received October 9, 2018
- Revision received November 24, 2018
- Accepted February 11, 2019
- Published online June 24, 2019.
- Xintong Jiang, MDa,∗,
- Feilong Wang, MDb,∗,
- Yajuan Wang, MD, PhDa,
- Anton Gisterå, MD, PhDa,
- Joy Roy, MD, PhDc,
- Gabrielle Paulsson-Berne, PhDa,
- Ulf Hedin, MD, PhDc,
- Amir Lerman, MDb,
- Göran K. Hansson, MD, PhDa,
- Joerg Herrmann, MDb,†∗ ( and )
- Zhong-qun Yan, MD, PhDa,†∗∗ ()
- aExperimental Cardiovascular Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
- bDepartment of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota
- cDepartment of Vascular Surgery, Karolinska University Hospital, Stockholm, Sweden
• Genetic and functional evidence suggests that there are additional inflammasome pathways, besides NLRP3, that contribute to IL-1 generation in human atherosclerotic plaques.
• Plaque generation of mature IL-1β is accompanied by secretion of similar levels of IL-1α, through a mechanism controlled by NLRP3 and caspase-1.
• Plaque IL-1β production is higher in patients with uncontrolled hyperlipidemia, on no or low-dose statin therapy, or with complex plaque imaging features.
• The present study lends support to high-intensity cholesterol lowering and anti-IL-1-directed therapies for patients at high cardiovascular risk.
CANTOS (Canakinumab Antiinflammatory Thrombosis Outcome Study) confirmed interleukin (IL)–1β as an appealing therapeutic target for human atherosclerosis and related complications. However, there are serious gaps in our understanding of IL-1 production in atherosclerosis. Herein the authors show that complex plaques, or plaques derived from patients with suboptimally controlled hyperlipidemia, or on no or low-intensity statin therapy, demonstrated higher recruitable IL-1β production. Generation of mature IL-1β was matched by IL-1α release, and both were attenuated by inhibition of NLR family pyrin domain containing 3 or caspase. These findings support the inflammasome as the main pathway for IL-1α/β generation in atherosclerosis and high-intensity lipid-lowering therapies as primary and additional anti-IL-1-directed therapies as secondary interventions in high-risk patients.
↵∗ Drs. Jiang and Wang contributed equally to this work and are joint first authors.
↵† Drs. Herrmann and Yan contributed equally to this work and are joint senior authors.
This work was supported by the KI-Mayo collaboration project, the Swedish Research Council, the Swedish Heart-Lung Foundation, European Union Seventh Framework Programme projects AtheroFlux (HEALTH-F2-2013-602222) and VIA (HEALTH-F2-2013- 603131), the Foundation for Strategic Research in Sweden, and the National Institutes of Health (HL116952-04). Dr. Jiang was supported by the Chinese Scholarship Council. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and U.S. Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received October 9, 2018.
- Revision received November 24, 2018.
- Accepted February 11, 2019.
- 2019 The Authors