RT Journal Article
T1 Role of TLR4 (Toll-Like Receptor 4) in N1/N2 Neutrophil Programming After Stroke
A1 García Culebras, Alicia
A1 Durán Laforet, Violeta
A1 Peña Martínez, Carolina Belén
A1 Moraga Yébenes, Ana
A1 Ballesteros Martín, Iván
A1 Cuartero Desviat, María Isabel
A1 Parra Gonzalo, Juan De La
A1 Palma Tortosa, Sara
A1 Hidalgo, Andrés
A1 Corbí, Ángel L.
A1 Moro Sánchez, María Ángeles
A1 Lizasoaín Hernández, Ignacio
AB Background and Purpose- After stroke, the population of infiltrated neutrophils in the brain is heterogeneous, including a population of alternative neutrophils (N2) that express M2 phenotype markers. We explored the role of TLR4 (toll-like receptor 4) on neutrophil infiltration and polarization in this setting. Methods- Focal cerebral ischemia was induced by occlusion of the middle cerebral artery occlusion in TLR4-KO and WT (wild type) mice. Infarct size was measured by Nissl staining and magnetic resonance imaging. Leukocyte infiltration was quantified 48 hours after middle cerebral artery occlusion by immunofluorescence and flow cytometry. To elucidate mechanisms underlying TLR4-mediated N2 phenotype, a cDNA microarray analysis was performed in neutrophils isolated from blood 48 hours after stroke in WT and TLR4-KO mice. Results- As demonstrated previously, TLR4-deficient mice presented lesser infarct volumes than WT mice. TLR4-deficient mice showed higher density of infiltrated neutrophils 48 hours after stroke compared with WT mice, concomitantly to neuroprotection. Furthermore, cytometric and stereological analyses revealed an increased number of N2 neutrophils (YM1+ cells) into the ischemic core in TLR4-deficient mice, suggesting a protective effect of this neutrophil subset that was corroborated by depleting peripheral neutrophils or using mice with TLR4 genetically ablated in the myeloid lineage. Finally, cDNA microarray analysis in neutrophils, confirmed by quantitative polymerase chain reaction, showed that TLR4 modulates several pathways associated with ischemia-induced inflammation, migration of neutrophils into the parenchyma, and their functional priming, which might explain the opposite effect on outcome of the different neutrophil subsets. Conclusions- TLR4 deficiency increased the levels of alternative neutrophils (N2)-an effect associated with neuroprotection after stroke-supporting that modulation of neutrophil polarization is a major target of TLR4 and highlighting the crucial role of TLR4 at the peripheral level after stroke. Visual Overview- An online visual overview is available for this article.
PB Lippincott, Williams & Wilkins
SN 0039-2499
SN 1524-4628
YR 2019
FD 2019-10
LK https://hdl.handle.net/20.500.14352/96292
UL https://hdl.handle.net/20.500.14352/96292
LA eng
NO García-Culebras A, Durán-Laforet V, Peña-Martínez C, Moraga A, Ballesteros I, Cuartero MI, de la Parra J, Palma-Tortosa S, Hidalgo A, Corbí AL, Moro MA, Lizasoain I. Role of TLR4 (Toll-Like Receptor 4) in N1/N2 Neutrophil Programming After Stroke. Stroke. 2019 Oct;50(10):2922-2932. doi: 10.1161/STROKEAHA.119.025085
DS Docta Complutense
RD 27 abr 2025