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

Isaac Francos-Quijorna, Marina Sánchez-Petidier, Emily R. Burnside, Smaranda R. Badea, Abel Torres-Espin, Lucy Marshall, Fred Winter, Joost Verhaagen, Victoria Moreno-Manzano and Elizabeth J. Bradbury ()
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Isaac Francos-Quijorna: Institute of Psychiatry, Psychology & Neuroscience
Marina Sánchez-Petidier: Prince Felipe Research Center, Carrer d´Eduardo Primo Yúfera 3
Emily R. Burnside: Institute of Psychiatry, Psychology & Neuroscience
Smaranda R. Badea: Institute of Psychiatry, Psychology & Neuroscience
Abel Torres-Espin: University of California San Francisco
Lucy Marshall: Institute of Psychiatry, Psychology & Neuroscience
Fred Winter: Royal Netherlands Academy of Sciences
Joost Verhaagen: Royal Netherlands Academy of Sciences
Victoria Moreno-Manzano: Prince Felipe Research Center, Carrer d´Eduardo Primo Yúfera 3
Elizabeth J. Bradbury: Institute of Psychiatry, Psychology & Neuroscience

Nature Communications, 2022, vol. 13, issue 1, 1-23

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30467-5

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