Hypoxia Promotes Neutrophil Survival After Acute Myocardial Infarction.

Maximilian Dölling,Xiaomei Shan,Markus Eckstein,Luis E Muñoz,Martin Herrmann,Jasmin Knopf,Aline Bozec,Georg Schett,Jeeshan Singh,Christine Schauer,Janina Schoen

doi:10.3389/fimmu.2022.726153

Abstract

Phagocytosis, degranulation, and neutrophil extracellular traps (NETs) formation build the armory of neutrophils for the first line of defense against invading pathogens. All these processes are modulated by the microenvironment including tonicity, pH and oxygen levels. Here we investigated the neutrophil infiltration in cardiac tissue autopsy samples of patients with acute myocardial infarction (AMI) and compared these with tissues from patients with sepsis, endocarditis, dermal inflammation, abscesses and diseases with prominent neutrophil infiltration. We observed many neutrophils infiltrating the heart muscle after myocardial infarction. Most of these had viable morphology and only few showed signs of nuclear de-condensation, a hallmark of early NET formation. The abundance of NETs was the lowest in acute myocardial infarction when compared to other examined diseases. Since cardiac oxygen supply is abruptly abrogated in acute myocardial infarction, we hypothesized that the resulting tissue hypoxia increased the longevity of the neutrophils. Indeed, the viable cells showed increased nuclear hypoxia inducible factor-1α (HIF-1α) content, and only neutrophils with low HIF-1α started the process of NET formation (chromatin de-condensation and nuclear swelling). Prolonged neutrophil survival, increased oxidative burst and reduced NETs formation were reproduced under low oxygen tensions and by HIF-1α stabilization in vitro. We conclude that nuclear HIF-1α is associated with prolonged neutrophil survival and enhanced oxidative stress in hypoxic areas of AMI.

Highlights

Neutrophils are the first circulating cells to respond to microbial attacks or tissue damage
The formation of Neutrophil Extracellular Traps (NETs) suppose the destruction of the neutrophil and the loss of other important defensive functions like degranulation and phagocytosis
We sought to evaluate the factors contributing to the decision of the neutrophil to form NETs based on the pattern of appearance of neutrophils, NETs and hypoxia inducible factor-1a (HIF-1a), the key factor in cell response to hypoxia, in human tissues

Summary

Introduction

Neutrophils are the first circulating cells to respond to microbial attacks or tissue damage. They initiate and orchestrate the inflammatory response [1]. Besides performing phagocytosis and degranulation, neutrophils are capable to externalize chromatin and form Neutrophil Extracellular Traps (NETs) at sites of inflammation [2]. Hypoxia Inhibits NET Formation with a plethora of nuclear and granular proteins; several of these display enzymatic activities. NET formation is proinflammatory, at high neutrophil densities the NETs tend to aggregate and form aggregated NETs (aggNETs). The latter are endowed with robust proteolytic activities that degrade various soluble cytokine and toxic compounds in the resolution phase of inflammation [3–5]

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