NK cells promote cardiac cell death and regulate myelopoiesis in myocardial infarction
Abstract
Abstract Ischemic heart failure remains a major clinical challenge, underscoring the need to better understand post-infarction immune mechanisms and identify new therapeutic targets. Both innate and adaptive immunity contribute to adverse cardiac remodeling following myocardial infarction (MI), yet the role of cytotoxic cells such as natural killer (NK) cells remains poorly defined. Here, we show that after acute MI in mice, NK cells are recruited to the ischemic myocardium in a CCR2-dependent manner and become activated. Activated NK cells locally release granzyme B, promoting cardiomyocyte apoptosis, adverse ventricular remodeling, and impaired cardiac function. Genetic deletion or pharmacological depletion of NK cells reduces cardiomyocyte death, attenuates inflammation, limits myocardial injury, and improves cardiac function. In contrast, NK cell activation using an anti-NKG2A monoclonal antibody exacerbates ischemic heart failure. We further demonstrate that NK cells regulate bone marrow myelopoiesis through local GM-CSF production. Finally, we identify a distinct NK cellular and transcriptomic signature in human ischemic heart tissue at early stages. Together, these findings reveal a detrimental role for NK cells following acute MI and highlight NK cells as potential therapeutic targets to limit adverse cardiac remodeling.
Article Details
Authors (33)
Raphael Cohen
Vincent Duval
Rida Al-Rifai
Sidrah Maryam
Icia Santos-Zas
Rayan Braïk
Marc Diedisheim
Charlène Jouve
Simon Nicoletti
Sara Thietart
Théo Guyon
Luna Chetrit
Maria Kral
Yvonne Döring
Christian Weber
Alexandre Loupy
Orianne Domenge
Marine Livrozet
Jean-Sébastien Hulot
Ecem T. Sakalli
Giuseppe Rizzo
Antoine-Emmanuel Saliba
Marie Piollet
Patrick Bruneval
Alain Tedgui
Soraya Taleb
Olivier Hermine
Ian Wicks
Jean-Sébastien Silvestre
Sikander Hayat
Clement Cochain
Eric Vivier
Hafid Ait-Oufella