Self-recruited Neutrophils Trigger Over-activated Innate Immune Response and Phenotypic Change of Cardiomyocytes in Fulminant Viral Myocarditis

Overview

Journal Cell Discov

Date 2023 Oct 10

PMID 37816761

Authors

Huihui Li

Mingzhi Zhang

Quanyi Zhao

Wanqing Zhao

Yan Zhuang

Jin Wang

Weijian Hang

Zheng Wen

Li Wang

Chen Chen

Dao Wen Wang

Affiliations

Soon will be listed here.

Abstract

Fulminant myocarditis (FM) is a life-threatening inflammatory disease. However, the mechanisms underlying its acute onset are unknown. By dynamic cardiac function measurement, we discovered that the initiation of sudden hemodynamic collapse was on day 4 in the mouse model of FM. Single-cell RNA-sequencing study revealed that healthy cardiomyocytes (CMs) lost their contractile and metabolic function and differentiated into pro-angiogenic and pro-inflammatory CMs. Meanwhile, neutrophils, the most expanded immune cells, exhibited a unique developmental trajectory only after migrating to the heart, where they continuously attracted peripheral neutrophils via Cxcl2/Cxcl3, resulting in the acute accumulation of neutrophils in the heart. Well-differentiated cardiac-infiltrating neutrophils, rather than viruses, induced phenotypic changes in CMs. Moreover, neutrophils could amplify cytokine storm by recruiting and activating pro-inflammatory monocytes. Blockade of the self-recruiting loop of neutrophils by targeting the Cxcl2/Cxcl3-Cxcr2 axis substantially alleviated FM in mice. Collectively, we provide a comprehensive single-cell atlas of immune cells and CMs in FM, elucidate the disease pathogenesis, and suggest potential therapeutic strategies.

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