1. Chondroitin sulfate proteoglycans prevent immune cell phenotypic conversion and inflammation resolution via TLR4 in rodent models of spinal cord injury
- Author
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Isaac Francos-Quijorna, Marina Sánchez-Petidier, Emily R. Burnside, Smaranda R. Badea, Abel Torres-Espin, Lucy Marshall, Fred de Winter, Joost Verhaagen, Victoria Moreno-Manzano, Elizabeth J. Bradbury, Molecular and Cellular Neurobiology, Amsterdam Neuroscience - Neurodegeneration, and Netherlands Institute for Neuroscience (NIN)
- Subjects
Inflammation ,Multidisciplinary ,animal structures ,General Physics and Astronomy ,Rodentia ,genetics [Toll-Like Receptor 4] ,General Chemistry ,Spinal Cord Injuries/pathology ,General Biochemistry, Genetics and Molecular Biology ,Toll-Like Receptor 4 ,Chondroitin Sulfate Proteoglycans/metabolism ,Chondroitin Sulfate Proteoglycans ,SDG 3 - Good Health and Well-being ,Animals ,ddc:500 ,metabolism [Chondroitin Sulfate Proteoglycans] ,pathology [Spinal Cord Injuries] ,Spinal Cord Injuries ,Toll-Like Receptor 4/genetics - 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.
- Published
- 2022
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