Self-recruited neutrophils trigger over-activated innate immune response and phenotypic change of cardiomyocytes in fulminant viral myocarditis

Author:

Li HuihuiORCID,Zhang Mingzhi,Zhao Quanyi,Zhao Wanqing,Zhuang Yan,Wang Jin,Hang Weijian,Wen Zheng,Wang LiORCID,Chen ChenORCID,Wang Dao WenORCID

Abstract

AbstractFulminant 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.

Funder

National Natural Science Foundation of China

Publisher

Springer Science and Business Media LLC

Subject

Cell Biology,Genetics,Molecular Biology,Biochemistry

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