Polymorphonuclear Cells Show Features of Dysfunctional Activation During Fatal Sepsis.

Marcela Hortová-Kohoutková,Ondřej Polanský,Veronika Tomášková,Ivana Andrejčinová,Vladimír Šrámek,Marco De Zuani,Martin Helán,Kamila Kočí,Kamila Bendíčková,Ondřej Mrkva,Petra Lázničková,Alexandra Mýtniková,Jan Frič

doi:10.3389/fimmu.2021.741484

Marcela Hortová-Kohoutková, Ondřej Polanský + Show 11 more

Open Access

https://doi.org/10.3389/fimmu.2021.741484

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Abstract

Sepsis and septic shock remain leading causes of morbidity and mortality for patients in the intensive care unit. During the early phase, immune cells produce various cytokines leading to prompt activation of the immune system. Polymorphonuclear leukocytes (PMNs) respond to different signals producing inflammatory factors and executing their antimicrobial mechanisms, resulting in the engulfment and elimination of invading pathogens. However, excessive activation caused by various inflammatory signals produced during sepsis progression can lead to the alteration of PMN signaling and subsequent defects in their functionality. Here, we analyzed samples from 34 patients in septic shock, focusing on PMNs gene expression and proteome changes associated with septic shock. We revealed that, compared to those patients who survived longer than five days, PMNs from patients who had fulminant sepsis were characterized by a dysfunctional hyper-activation, show altered metabolism, and recent exit from the cell cycle and signs of cellular lifespan. We believe that this multi-omics approach, although limited, pinpoints the alterations in PMNs’ functionality, which may be rescued by targeted treatments.

Highlights

Sepsis is a highly heterogeneous, life-threatening organ dysfunction mainly caused by the dysregulated host response to infection
Polymorphonuclear leukocytes (PMNs) From Early Deceased Patients Show Signs of Early Hyperactivation To determine the changes in the transcriptome of PMNs during septic shock, we performed bulk RNAseq of PMNs isolated from patients affected by septic shock at two different time points: within hours (TP1) and 5 days (TP2) from Intensive care unit (ICU) admission
To determine the changes in PMN phenotype detectable at the time of admissions leading to early death in ICU, we divided our cohort into two groups: early deceased patients and patients that survived for more than 5 days

Summary

Introduction

Sepsis is a highly heterogeneous, life-threatening organ dysfunction mainly caused by the dysregulated host response to infection. Making up 40% to 60% of total circulating white blood cells, neutrophils are among the first responders during infection and are known to play a key role in the onset and progression of sepsis [5]. These cells are equipped with a wide plethora of innate receptors and antimicrobial molecules and can quickly invade the sites of Polymorphonuclears in Septic Shock inflammation where they eradicate pathogens through phagocytosis and the release of neutrophil extracellular traps (NETs) [6]. Through transcriptomic and proteomic approaches, we analyzed the phenotypic hallmarks of the PMN pool that are associated with a fulminant death in the Intensive care unit (ICU) or to survival

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