Autologous cryo-shocked neutrophils enable targeted therapy of sepsis via broad-spectrum neutralization of pro-inflammatory cytokines and endotoxins

Qiuxia Gao; Yan Yan; Jie Zhang; Xiaoxue Li; Jiamei Wang; Yi Feng; Peiran Li; Huanhuan Wang; Yunlong Zhang; Lingjie He; Zhiyan Shan; Bin Li

doi:10.3389/fchem.2024.1359946

Autologous cryo-shocked neutrophils enable targeted therapy of sepsis via broad-spectrum neutralization of pro-inflammatory cytokines and endotoxins

Front Chem. 2024 Feb 21:12:1359946. doi: 10.3389/fchem.2024.1359946. eCollection 2024.

Authors

Qiuxia Gao^#^{1

2

3}, Yan Yan^#⁴, Jie Zhang^#⁵, Xiaoxue Li³, Jiamei Wang³, Yi Feng³, Peiran Li³, Huanhuan Wang³, Yunlong Zhang⁴, Lingjie He³, Zhiyan Shan⁶, Bin Li^{1

2}

Affiliations

¹ School of Inspection, Ningxia Medical University, Yinchuan, Ningxia, China.
² Institute of Translational Medicine, The First People's Hospital of Foshan, Foshan, Guangdong, China.
³ Molecular Diagnosis and Treatment Center for Infectious Diseases, Dermatology Hospital of Southern Medical University, Guangzhou, Guangdong, China.
⁴ Department of Critical Care Medicine, Department of Emergency, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
⁵ Engineering Research Center of Tibetan Medicine Detection Technology, Ministry of Education, Xizang Minzu University, Xianyang, Shaanxi, China.
⁶ Department of Histology and Embryology, Harbin Medical University, Harbin, Heilongjiang, China.

^# Contributed equally.

Abstract

Background: Sepsis is a life-threatening disease characterized by multiple organ failure due to excessive activation of the inflammatory response and cytokine storm. Despite recent advances in the clinical use of anti-cytokine biologics, sepsis treatment efficacy and improvements in mortality remain unsatisfactory, largely due to the mechanistic complexity of immune regulation and cytokine interactions. Methods: In this study, a broad-spectrum anti-inflammatory and endotoxin neutralization strategy was developed based on autologous "cryo-shocked" neutrophils (CS-Neus) for the management of sepsis. Neutrophils were frozen to death using a novel liquid nitrogen "cryo-shock" strategy. The CS-Neus retained the source cell membrane structure and functions related to inflammatory site targeting, broad-spectrum inflammatory cytokines, and endotoxin (LPS) neutralizing properties. This strategy aimed to disable harmful pro-inflammatory functions of neutrophils, such as cytokine secretion. Autologous cell-based therapy strategies were employed to avoid immune rejection and enhance treatment safety. Results: In both LPS-induced sepsis mouse models and clinical patient-derived blood samples, CS-Neus treatment significantly ameliorated cytokine storms by removing inflammatory cytokines and endotoxin. The therapy showed notable anti-inflammatory therapeutic effects and improved the survival rate of mice. Discussion: The results of this study demonstrate the potential of autologous "cryo-shocked" neutrophils as a promising therapeutic approach for managing sepsis. By targeting inflammatory organs and exhibiting anti-inflammatory activity, CS-Neus offer a novel strategy to combat the complexities of sepsis treatment. Further research and clinical trials are needed to validate the efficacy and safety of this approach in broader populations and settings.

Keywords: broad-spectrum anti-inflammatory; cryo-shock; cytokine storm; endotoxin; neutrophils; sepsis.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Key Research and Development Program of China (2021YFC2302200), the National Natural Science Foundation of China (82272248, 81972019, 32170939, 82371846, 32170939, and 52122317), the China Postdoctoral Science Foundation (2022M720730 and 2021M690634), the Natural Science Foundation of Guangdong Province for Distinguished Young Scholars (2022B1515020089), the Basic and Applied Basic Research Foundation of Guangdong Province (2021A1515110209, 2022A1515140080, 2022B1515020075, 2021B1515120036, and 2020A1515110529), the Comprehensive Research Project of the National Natural Science Foundation of China (82241059), the Zhongnanshan Medical Foundation of Guangdong Province (ZNSA2021012), and the Training project of National Science Foundation for Outstanding/Distinguished Young Scholars of Southern Medical University (C620PF0217).