Diverse NKT cells regulate early inflammation and neurological outcomes after cardiac arrest and resuscitation
Neurological injury drives most deaths and morbidity among patients hospitalized for out-of-hospital cardiac arrest (OHCA). Despite its clinical importance, there are no effective pharmacological therapies targeting post-cardiac arrest (CA) neurological injury. Here, we analyzed circulating immune cells from a large cohort of patients with OHCA, finding that lymphopenia independently associated with poor neurological outcomes. Single-cell RNA sequencing of immune cells showed that T cells with features of both innate T cells and natural killer (NK) cells were increased in patients with favorable neurological outcomes. We more specifically identified an early increase in circulating diverse NKT (dNKT) cells in a separate cohort of patients with OHCA who had good neurological outcomes. These cells harbored a diverse T cell receptor repertoire but were consistently specific for sulfatide antigen. In mice, we found that sulfatide-specific dNKT cells trafficked to the brain after CA and resuscitation. In the brains of mice lacking NKT cells (<i>Cd1d</i><sup>-/-</sup>), we observed increased inflammatory chemokine and cytokine expression and accumulation of macrophages when compared with wild-type mice. <i>Cd1d</i><sup>-/-</sup> mice also had increased neuronal injury, neurological dysfunction, and worse mortality after CA. To therapeutically enhance dNKT cell activity, we treated mice with sulfatide lipid after CA, showing that it improved neurological function. Together, these data show that sulfatide-specific dNKT cells are associated with good neurological outcomes after clinical OHCA and are neuroprotective in mice after CA. Strategies to enhance the number or function of dNKT cells may thus represent a treatment approach for CA.
Authors
- Raghu R. Seethala (ORCID: https://orcid.org/0000-0002-3501-7094)
- Jingyu Guo (ORCID: https://orcid.org/0000-0001-7700-6468)
- Edy Y. Kim (ORCID: https://orcid.org/0000-0002-9095-3109)
- Benjamin A. Olenchock (ORCID: https://orcid.org/0000-0002-8956-5117)
- Louis T. Merriam (ORCID: https://orcid.org/0000-0002-3731-6792)
- Muhammad Dawood Amir Sheikh (ORCID: https://orcid.org/0000-0002-5029-4161)
- Erin A. Bohula (ORCID: https://orcid.org/0000-0002-5559-8172)
- Tyler Rolland (ORCID: https://orcid.org/0000-0003-2700-8160)
- Aidan M. Cullen
- Brent R. Weil (ORCID: https://orcid.org/0000-0002-0289-5771)
- Xi Chen (ORCID: https://orcid.org/0000-0001-8127-6014)
- Changde Cheng (ORCID: https://orcid.org/0000-0002-2458-2522)
- Jaivardhan A. Menon (ORCID: https://orcid.org/0000-0002-8332-5198)
- Patrick R. Lawler (ORCID: https://orcid.org/0000-0001-5155-5071)
- Mayra Pinilla-Vera
- Jack Varon (ORCID: https://orcid.org/0000-0001-8132-0222)
- Reshmi Manandhar
- Alexandra Weissman (ORCID: https://orcid.org/0000-0002-3350-899X)
- Hyun Soon Sohn (ORCID: https://orcid.org/0000-0003-1360-1895)
- Kei Hayashida (ORCID: https://orcid.org/0000-0002-2287-3318)
- Ana B. Villasenõr-Altamirano (ORCID: https://orcid.org/0000-0002-3940-5617)
- Xi Lin (ORCID: https://orcid.org/0000-0003-2526-5163)
- Richard S. Blumberg (ORCID: https://orcid.org/0000-0002-9704-248X)
- Tomoyoshi Tamura (ORCID: https://orcid.org/0000-0001-7435-6534)
- David A. Morrow (ORCID: https://orcid.org/0000-0002-9589-5382)
- Fumito Ichinose (ORCID: https://orcid.org/0000-0003-4535-1632)
- Jiyoung Choi
- Rebecca M. Baron (ORCID: https://orcid.org/0000-0003-1673-9523)
- William M. Oldham (ORCID: https://orcid.org/0000-0003-3029-4866)
- Peter C. Hou (ORCID: https://orcid.org/0000-0002-7726-2901)
- Kohei Ikeda (ORCID: https://orcid.org/0000-0002-0961-1532)
- Hattie Chung (ORCID: https://orcid.org/0000-0001-8417-5606)
- Fei Chen (ORCID: https://orcid.org/0000-0003-2308-3649)
- Xiang Chen (ORCID: https://orcid.org/0000-0002-2499-8261)
- Jiani Chen (ORCID: https://orcid.org/0000-0002-3560-2269)
- Kohei Yamada
- Michael B. Brenner
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- St. Jude Children's Research Hospital (US)
- Harvard University (US)
- University of Pittsburgh (US)
- University of Toronto (CA)
- Keio University (JP)
- McGill University Health Centre (CA)
- University of Alabama at Birmingham (US)
- Massachusetts General Hospital (US)
Publication Details
- Journal
- Science Translational Medicine
- Published
- 2024-12-04
- DOI
- https://doi.org/10.1126/scitranslmed.adq5796
- Citations
- 9
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 2.23
Funders
- American Heart Association
- American Lebanese Syrian Associated Charities
- Japan Heart Foundation
- National Institutes of Health
- Bayer Yakuhin
- Japan Society for the Promotion of Science
- National Heart, Lung, and Blood Institute
- National Cancer Institute
- National Institute of Diabetes and Digestive and Kidney Diseases