Details

Autor(en) / Beteiligte

• Tamura, Tomoyoshi
• Cheng, Changde
• Chen, Wenan
• Merriam, Louis T.
• Athar, Humra
• Kim, Yaunghyun H.
• Manandhar, Reshmi
• Amir Sheikh, Muhammad Dawood
• Pinilla-Vera, Mayra
• Varon, Jack
• Hou, Peter C.
• Lawler, Patrick R.
• Oldham, William M.
• Seethala, Raghu R.
• Tesfaigzi, Yohannes
• Weissman, Alexandra J.
• Baron, Rebecca M.
• Ichinose, Fumito
• Berg, Katherine M.
• Bohula, Erin A.
• Morrow, David A.
• Chen, Xiang
• Kim, Edy Y.

Titel

Single-cell transcriptomics reveal a hyperacute cytokine and immune checkpoint axis after cardiac arrest in patients with poor neurological outcome

Ist Teil von

• Med (New York, N.Y. : Online), 2023-07, Vol.4 (7), p.432-456.e6

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• Most patients hospitalized after cardiac arrest (CA) die because of neurological injury. The systemic inflammatory response after CA is associated with neurological injury and mortality but remains poorly defined. We determine the innate immune network induced by clinical CA at single-cell resolution. Immune cell states diverge as early as 6 h post-CA between patients with good or poor neurological outcomes 30 days after CA. Nectin-2+ monocyte and Tim-3+ natural killer (NK) cell subpopulations are associated with poor outcomes, and interactome analysis highlights their crosstalk via cytokines and immune checkpoints. Ex vivo studies of peripheral blood cells from CA patients demonstrate that immune checkpoints are a compensatory mechanism against inflammation after CA. Interferon γ (IFNγ)/interleukin-10 (IL-10) induced Nectin-2 on monocytes; in a negative feedback loop, Nectin-2 suppresses IFNγ production by NK cells. The initial hours after CA may represent a window for therapeutic intervention in the resolution of inflammation via immune checkpoints. This work was supported by funding from the American Heart Association, Brigham and Women’s Hospital Department of Medicine, the Evergreen Innovation Fund, and the National Institutes of Health. [Display omitted] •Early immune states after cardiac arrest are associated with neurological outcomes•Divergence of innate immune states is transient and lost by 48 h post-arrest•Nectin-2+ monocytes and Tim-3+ natural killer cells are associated with poor outcomes•IFNγ/IL-10 induce Nectin-2 on monocytes, which then suppress IFNγ+ NK cells Brain injury is the leading cause of death among patients hospitalized after out-of-hospital cardiac arrest. Although inflammation is associated with brain injury and mortality after cardiac arrest, the immune landscape after cardiac arrest is poorly understood. By examining peripheral blood at single-cell resolution, this study shows that examining the innate immune system just 6 h after cardiac arrest differentiates patients who eventually have good or poor neurological outcomes days later. Cardiac arrest triggers an early negative feedback loop in which pro- and anti-inflammatory cytokines induce immune checkpoints that limit inflammation. These findings support investigation of therapeutic approaches that augment protective immune mechanisms very early after cardiac arrest. Tamura et al. study the gap in knowledge of immune responses after cardiac arrest. They use single-cell approaches to show that early divergence in innate immunity is associated with eventual neurological outcomes. Nectin-2+ monocytes suppress Tim-3+ natural killer cells via immune checkpoints as a compensatory, anti-inflammatory feedback loop after cardiac arrest.