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

Author

Listed:
  • Isaac Francos-Quijorna

    (Institute of Psychiatry, Psychology & Neuroscience
    Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM))

  • Marina Sánchez-Petidier

    (Prince Felipe Research Center, Carrer d´Eduardo Primo Yúfera 3)

  • Emily R. Burnside

    (Institute of Psychiatry, Psychology & Neuroscience
    German Center for Neurodegenerative Diseases (DZNE))

  • 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
    Vrije Universiteit Amsterdam)

  • Victoria Moreno-Manzano

    (Prince Felipe Research Center, Carrer d´Eduardo Primo Yúfera 3)

  • Elizabeth J. Bradbury

    (Institute of Psychiatry, Psychology & Neuroscience)

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.

Suggested Citation

  • Isaac Francos-Quijorna & Marina Sánchez-Petidier & Emily R. Burnside & Smaranda R. Badea & Abel Torres-Espin & Lucy Marshall & Fred Winter & Joost Verhaagen & Victoria Moreno-Manzano & Elizabeth J. Br, 2022. "Chondroitin sulfate proteoglycans prevent immune cell phenotypic conversion and inflammation resolution via TLR4 in rodent models of spinal cord injury," Nature Communications, Nature, vol. 13(1), pages 1-23, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30467-5
    DOI: 10.1038/s41467-022-30467-5
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