Neutrophil extracellular traps formation and clearance is enhanced in fever and attenuated in hypothermia

Jakub Janko; Emil Bečka; Katarína Kmeťová; Letícia Hudecová; Barbora Konečná; Peter Celec; Mona Bajaj-Elliott; Michal Pastorek

doi:10.3389/fimmu.2023.1257422

Neutrophil extracellular traps formation and clearance is enhanced in fever and attenuated in hypothermia

Front Immunol. 2023 Oct 2:14:1257422. doi: 10.3389/fimmu.2023.1257422. eCollection 2023.

Authors

Jakub Janko¹, Emil Bečka¹, Katarína Kmeťová¹, Letícia Hudecová¹, Barbora Konečná¹, Peter Celec^{1

2}, Mona Bajaj-Elliott³, Michal Pastorek¹

Affiliations

¹ Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
² Institute of Pathophysiology, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
³ Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.

Abstract

Fever and hypothermia represent two opposite strategies for fighting systemic inflammation. Fever results in immune activation; hypothermia is associated with energy conservation. Systemic Inflammatory Response Syndrome (SIRS) remains a significant cause of mortality worldwide. SIRS can lead to a broad spectrum of clinical symptoms but importantly, patients can develop fever or hypothermia. During infection, polymorphonuclear cells (PMNs) such as neutrophils prevent pathogen dissemination through the formation of neutrophil extracellular traps (NETs) that ensnare and kill bacteria. However, when dysregulated, NETs also promote host tissue damage. Herein, we tested the hypothesis that temperature modulates NETs homeostasis in response to infection and inflammation. NETs formation was studied in response to infectious (Escherichia coli, Staphylococcus aureus) and sterile (mitochondria) agents. When compared to body temperature (37°C), NETs formation increased at 40°C; interestingly, the response was stunted at 35°C and 42°C. While CD16+ CD49d+ PMNs represent a small proportion of the neutrophil population, they formed ~45-85% of NETs irrespective of temperature. Temperature increased formyl peptide receptor 1 (FPR1) expression to a differential extent in CD16+ CD49d- vs. CD49d+ PMNSs, suggesting further complexity to neutrophil function in hypo/hyperthermic conditions. The capacity of NETs to induce Toll-like receptor 9 (TLR9)-mediated NF-κB activation was found to be temperature independent. Interestingly, NET degradation was enhanced at higher temperatures, which corresponded with greater plasma DNase activity in response to temperature increase. Collectively, our observations indicate that NETs formation and clearance are enhanced at 40°C whilst temperatures of 35°C and 42°C attenuate this response. Targeting PMN-driven immunity may represent new venues for intervention in pathological inflammation.

Keywords: DNase I; bacteria; fever; hypothermia; mitochondria; neutrophil extracellular trap; polymorphonuclear cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Extracellular Traps*
Humans
Hypothermia* / metabolism
Hypothermia* / pathology
Inflammation / metabolism
Neutrophils
Systemic Inflammatory Response Syndrome / pathology

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants from The Slovak Research and Development Agency No. APVV-21-0378, the Grant Agency of Ministry of Education, Science, Research and Sport of the Slovak Republic No. VEGA 1/0716/20.