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

Research output: Contribution to journalArticlepeer-review

Elizabeth Bradbury, Isaac Francos Quijorna, Emily Burnside, Smaranda Badea, Lucy Marshall, Marina Sánchez-Petidier, Victoria Moreno-Manzano, Abel Torres-Espin, Fred de Winter, Joost Verhaagen

Original languageEnglish
JournalNature Communications
Accepted/In press9 May 2022

King's Authors


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. 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. 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, which leads to prolonged inflammatory pathology and irreversible tissue destruction.

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