Abstract

Background and PurposeThe immune response subsequent to an ischemic stroke is a crucial factor in its physiopathology and outcome. It is known that TLR4 is implicated in brain damage and inflammation after stroke and that TLR4 absence induces neutrophil reprogramming toward a protective phenotype in brain ischemia, but the mechanisms remain unknown. We therefore asked how the lack of TLR4 modifies neutrophil function and their contribution to the inflammatory process.MethodsIn order to assess the role of the neutrophilic TLR4 after stroke, mice that do not express TLR4 in myeloid cells (TLR4loxP/Lyz-cre) and its respective controls (TLR4loxP/loxP) were used. Focal cerebral ischemia was induced by occlusion of the middle cerebral artery and infarct size was measured by MRI. A combination of flow cytometry and confocal microscopy was used to assess different neutrophil characteristics (circadian fluctuation, cell surface markers, cell complexity) and functions (apoptosis, microglia engulfment, phagocytosis, NETosis, oxidative burst) in both genotypes.ResultsAs previously demonstrated, mice with TLR4 lacking-neutrophils had smaller infarct volumes than control mice. Our results show that the absence of TLR4 keeps neutrophils in a steady youth status that is dysregulated, at least in part, after an ischemic insult, preventing neutrophils from their normal circadian fluctuation. TLR4-lacking neutrophils showed a higher phagocytic activity in the basal state, they were preferentially engulfed by the microglia after stroke, and they produced less radical oxygen species (ROS) in the first stage of the inflammatory process.ConclusionsTLR4 is specifically involved in neutrophil dynamics under physiological conditions as well as in stroke-induced tissue damage. This research contributes to the idea that TLR4, especially when targeted in specific cell types, is a potential target for neuroprotective strategies.

Highlights

  • Stroke is the leading cause of death and disability world-wide

  • In order to assess the role of Toll-Like Receptor 4 (TLR4) on neutrophil function after stroke, TLR4loxP/loxP and TLR4loxP/Lyz-cre mice were subjected to pMCAO

  • TLR4loxP/Lyz-cre mice showed a reduced infarct volume determined by magnetic resonance imaging 24 h after the surgery (Supplemental Figure 1A, P < 0.05)

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Summary

Introduction

Stroke is the leading cause of death and disability world-wide. It affects 13.7 million people globally per year and causes 5.5 million deaths which means that an estimated of 1 in 4 adults will experience a stroke in their lifetime [1]. The immune response subsequent to an ischemic stroke is a crucial factor in stroke physiopathology and outcome. Several studies have proven that the lack of TLR4 entitles improved neurological and behavioral outcomes in different animal models of experimental stroke [4, 5]. This fact has been demonstrated in patients, in which the upregulation of TLR4 correlates with higher inflammation and poor outcome [6]. The immune response subsequent to an ischemic stroke is a crucial factor in its physiopathology and outcome. We asked how the lack of TLR4 modifies neutrophil function and their contribution to the inflammatory process

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