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This work was supported by grants from the Instituto de Salud Carlos III (ISCIII) (Programa Miguel Servet II Grants CPII19/00005; PI16/00735; PI19/00082 to JE; and PI18/00357 to DC, partially funded by FEDER - European Union 'Una manera de hacer Europa') and Fundacion Mutua Madrilena to JE; European Union's Horizon 2020 research and innovation programme under the H2020 Marie Skodowska-Curie Actions grant agreement no. 794926 and Stop Fuga de Cerebros Roche Pharma to JMR; and Ministerio de Ciencia e Innovacion RTI2018-094887-B-I00 and RYC-2016-20414 to MN and RYC2019-026870-I to JMR. DC, MCO, VVS and EFL are hired by SESCAM. We also thank Dr. Ju Chen (University of California, San Diego, CA, USA) and Dr. Gertrudis Perea (Cajal Institute, Madrid, Spain) for kindly providing IP3R2-/- animals and Dr. Juan Aguilar (HNP, Toledo, Spain) for technical and scientific support.

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TLR4 pathway impairs synaptic number and cerebrovascular functions through astrocyte activation following traumatic brain injury

Publicado en:BRITISH JOURNAL OF PHARMACOLOGY. 178 (17): 3395-3413 - 2021-09-01 178(17), DOI: 10.1111/bph.15488

Autores: Rosa, Juliana M.; Farre-Alins, Victor; Ortega, Maria Cristina; Navarrete, Marta; Lopez-Rodriguez, Ana Belen; Palomino-Antolin, Alejandra; Fernandez-Lopez, Elena; Vila-del Sol, Virginia; Decouty, Celine; Narros-Fernandez, Paloma; Clemente, Diego; Egea, Javier;

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Background and Purpose Activation of astrocytes contributes to synaptic remodelling, tissue repair and neuronal survival following traumatic brain injury (TBI). The mechanisms by which these cells interact to resident/infiltrated inflammatory cells to rewire neuronal networks and repair brain functions remain poorly understood. Here, we explored how TLR4-induced astrocyte activation modified synapses and cerebrovascular integrity following TBI. Experimental Approach To determine how functional astrocyte alterations induced by activation of TLR4 pathway in inflammatory cells regulate synapses and neurovascular integrity after TBI, we used pharmacology, genetic approaches, live calcium imaging, immunofluorescence, flow cytometry, blood-brain barrier (BBB) integrity assessment and molecular and behavioural methods. Key Results Shortly after a TBI, there is a recruitment of excitable and reactive astrocytes mediated by TLR4 pathway activation with detrimental effects on post-synaptic density-95 (PSD-95)/vesicular glutamate transporter 1 (VGLUT1) synaptic puncta, BBB integrity and neurological outcome. Pharmacological blockage of the TLR4 pathway with resatorvid (TAK-242) partially reversed many of the observed effects. Synapses and BBB recovery after resatorvid administration were not observed in IP(3)R2(-/-) mice, indicating that effects of TLR4 inhibition depend on the subsequent astrocyte activation. In addition, TBI increased the astrocytic-protein thrombospondin-1 necessary to induce a synaptic recovery in a sub-acute phase. Conclusions and Implications Our data demonstrate that TLR4-mediated signalling, most probably through microglia and/or infiltrated monocyte-astrocyte communication, plays a crucial role in the TBI pathophysiology and that its inhibition prevents synaptic loss and BBB damage accelerating tissue recovery/repair, which might represent a therapeutic potential in CNS injuries and disorders.

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