Activated Platelets Autocrine 5-Hydroxytryptophan Aggravates Sepsis-Induced Acute Lung Injury by Promoting Neutrophils Extracellular Traps Formation.

Yumeng Huang,Jia Gu,Shuangwei Chen,Shengqiao Fu,Qian Ji,Liangmei Chu,Ningzheng Tai,Dadong Liu,Yongfei Ren,Yue Wang,Yanyan Zhu,Xuan Lei

doi:10.3389/fcell.2021.777989

Abstract

Excessive neutrophil extracellular trap (NET) formation is an important contributor to sepsis-induced acute lung injury (ALI). Recent reports indicate that platelets can induce neutrophil extracellular trap formation. However, the specific mechanism remains unclear. Tph1 gene, which encodes the rate-limiting enzyme for peripheral 5-hydroxytryptophan (5-HT) synthesis, was knocked out in mice to simulate peripheral 5-HT deficiency. Cecal ligation and puncture (CLP) surgery was performed to induce sepsis. We found that peripheral 5-HT deficiency reduced NET formation in lung tissues, alleviated sepsis-induced lung inflammatory injury, and reduced the mortality rate of CLP mice. In addition, peripheral 5-HT deficiency was shown to reduce the accumulation of platelets and NETs in the lung of septic mice. We found that platelets from wild-type (WT), but not Tph1 knockout (Tph1 −/− ), mice promote lipopolysaccharide (LPS)-induced NET formation. Exogenous 5-HT intervention increased LPS-induced NET formation when Tph1 −/− platelets were co-cultured with WT neutrophils. Therefore, our study uncovers a mechanism by which peripheral 5-HT aggravated sepsis-induced ALI by promoting NET formation in the lung of septic mice.

Highlights

Sepsis is a life-threatening organ dysfunction caused by the host’s unbalanced response to infection and continues to be a major cause of death resulting from infection (Fleischmann et al, 2016; Rhodes et al, 2017; Napolitano 2018; Xie et al, 2020)
We found that Tph1−/− cecal ligation and puncture (CLP) mice had a minor increase in Bronchoalveolar lavage fluid (BALF) TNF-α and interleukin 6 (IL-6)
neutrophil extracellular trap (NET) are extracellular strands of decondensed DNA that are decorated with histones and neutrophil granule proteins

Summary

Introduction

Sepsis is a life-threatening organ dysfunction caused by the host’s unbalanced response to infection and continues to be a major cause of death resulting from infection (Fleischmann et al, 2016; Rhodes et al, 2017; Napolitano 2018; Xie et al, 2020). The lungs are usually the earliest organ suffering in sepsis (Costa et al, 2006; Wang et al, 2019). 5-Hydroxytryptophan, Lung Injury, and NETs past years, it was believed that neutrophils kill bacteria through phagocytosis and degranulation (Kolaczkowska and Kubes, 2013). With the continuous research on NETs, some investigators indicated that excessive NET formation was an important cause of sepsis-induced organ dysfunction and death (Sonego et al, 2016; Ravindran et al, 2019; Tan et al, 2020). Sepsisinduced acute lung injury (ALI) can be accentuated by NETs (Jhelum et al, 2018; Wang et al, 2020; Yaqinuddin and Kashir, 2020).

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Conclusion