2026-07-23T17:11:49Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/182192024-09-21T09:48:46Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605
Repisalud
author
Durán-Laforet, Violeta
author
Peña-Martínez, Carolina
author
García-Culebras, Alicia
author
Cuartero, María Isabel
author
Lo, Eng H
author
Moro, María Ángeles
author
Lizasoain, Ignacio
funder
Instituto de Salud Carlos III
funder
Ministerio de Ciencia e Innovación (España)
funder
Fundación ProCNIC
funder
Fundación La Caixa
2024-02-19T10:50:22Z
2024-02-19T10:50:22Z
2021
Front Immunol. 2021 Oct 21:12:757872.
10.3389/fimmu.2021.757872
1664-3224
Frontiers in immunology
34745132
http://hdl.handle.net/20.500.12105/18219
BACKGROUND AND PURPOSE
The 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.
METHODS
In 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.
RESULTS
As 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.
CONCLUSIONS
TLR4 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.
eng
Role of TLR4 in Neutrophil Dynamics and Functions: Contribution to Stroke Pathophysiology.
journal article
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Role of TLR4 in Neutrophil_Front Immunol_2021.pdf
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Role of TLR4 in Neutrophil_Front Immunol_2021.pdf
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Role of TLR4 in Neutrophil_Front Immunol_2021.pdf.txt