Chondroitin sulfate proteoglycans prevent immune cell phenotypic conversion and inflammation resolution via TLR4 in rodent models of spinal cord injury.

Fecha de publicación: 25/05/2022

Autores de CIPF

M Victoria Moreno Manzano

Autor

Participantes ajenos a CIPF

Francos-Quijorna I
Sánchez-Petidier M
Burnside ER
Badea SR
Torres-Espin A
Marshall L
de Winter F
Verhaagen J
Bradbury EJ

Grupos de Investigación

Laboratorio de Regeneración Tisular y Neuronal

Jefe/a de Grupo

M Victoria Moreno Manzano

Abstract

Chondroitin sulfate proteoglycans (CSPGs) act as potent inhibitors of axonal growth and neuroplasticity after spinal cord injury (SCI). Here we reveal that CSPGs also play a critical role in preventing inflammation resolution by blocking the conversion of pro-inflammatory immune cells to a pro-repair phenotype in rodent models of SCI. We demonstrate that enzymatic digestion of CSPG glycosaminoglycans enhances immune cell clearance and reduces pro-inflammatory protein and gene expression profiles at key resolution time points. Analysis of phenotypically distinct immune cell clusters revealed CSPG-mediated modulation of macrophage and microglial subtypes which, together with T lymphocyte infiltration and composition changes, suggests a role for CSPGs in modulating both innate and adaptive immune responses after SCI. Mechanistically, CSPG activation of a pro-inflammatory phenotype in pro-repair immune cells was found to be TLR4-dependent, identifying TLR4 signalling as a key driver of CSPG-mediated immune modulation. These findings establish CSPGs as critical mediators of inflammation resolution failure after SCI in rodents, which leads to prolonged inflammatory pathology and irreversible tissue destruction.

Datos de la publicación

ISSN/ISSNe:: 2041-1723, 2041-1723
Tipo:: Article
Páginas:: 2933-2933
DOI:: 10.1038/s41467-022-30467-5
PubMed:: 35614038

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Métricas

Filiaciones

Francos-Quijorna I:: King's College London, Regeneration Group, The Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology & Neuroscience, Guy's Campus, London Bridge, London, SE1 1UL, UK

Immunometabolism and Inflammation Laboratory, Centro de Biología Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), 28049, Madrid, Spain
Sánchez-Petidier M:: Neuronal and Tissue Regeneration Laboratory, Prince Felipe Research Center, Carrer d´Eduardo Primo Yúfera 3, 46012, Valencia, Spain
Burnside ER:: King's College London, Regeneration Group, The Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology & Neuroscience, Guy's Campus, London Bridge, London, SE1 1UL, UK

Laboratory of Axonal Growth and Regeneration, German Center for Neurodegenerative Diseases (DZNE), Venusberg Campus 1/99, 53127, Bonn, Germany
Badea SR:: King's College London, Regeneration Group, The Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology & Neuroscience, Guy's Campus, London Bridge, London, SE1 1UL, UK
Torres-Espin A:: Brain and Spinal Injury Center, Neurological Surgery, University of California San Francisco, San Francisco, USA
Marshall L:: King's College London, Regeneration Group, The Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology & Neuroscience, Guy's Campus, London Bridge, London, SE1 1UL, UK
Moreno-Manzano V:: Neuronal and Tissue Regeneration Laboratory, Prince Felipe Research Center, Carrer d´Eduardo Primo Yúfera 3, 46012, Valencia, Spain
Bradbury EJ:: King's College London, Regeneration Group, The Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology & Neuroscience, Guy's Campus, London Bridge, London, SE1 1UL, UK.

Campos de Estudio

Proyectos asociados

Nuevo biomaterial bio-activo para la regeneración de lesiones medulares

Investigador Principal: M VICTORIA MORENO MANZANO

MINISTERIO DE ECON. Y COMPET. . 2019

Regeneration of Injured Spinal cord by Electro pUlsed bio-hybrid imPlant