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 de Winter; Joost Verhaagen; Victoria Moreno-Manzano; Elizabeth J Bradbury

doi:10.1038/s41467-022-30467-5

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 de Winter, Joost Verhaagen, Victoria Moreno-Manzano, Elizabeth J Bradbury

Netherlands Institute for Neuroscience (NIN)

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

36 Citations (Scopus)

54 Downloads (Pure)

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.

Original language	English
Pages (from-to)	2933
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-30467-5
Publication status	Published - 25 May 2022

Keywords

Animals
Chondroitin Sulfate Proteoglycans/metabolism
Inflammation
Rodentia
Spinal Cord Injuries/pathology
Toll-Like Receptor 4/genetics

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Francos-Quijorna, I., Sánchez-Petidier, M., Burnside, E. R., Badea, S. R., Torres-Espin, A., Marshall, L., de Winter, F., Verhaagen, J., Moreno-Manzano, V., & Bradbury, E. J. (2022). Chondroitin sulfate proteoglycans prevent immune cell phenotypic conversion and inflammation resolution via TLR4 in rodent models of spinal cord injury. Nature Communications, 13(1), 2933. https://doi.org/10.1038/s41467-022-30467-5

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

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.",

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author = "Isaac Francos-Quijorna and Marina S{\'a}nchez-Petidier and Burnside, {Emily R} and Badea, {Smaranda R} and Abel Torres-Espin and Lucy Marshall and {de Winter}, Fred and Joost Verhaagen and Victoria Moreno-Manzano and Bradbury, {Elizabeth J}",

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Francos-Quijorna, I, Sánchez-Petidier, M, Burnside, ER, Badea, SR, Torres-Espin, A, Marshall, L, de Winter, F , Verhaagen, J, Moreno-Manzano, V & Bradbury, EJ 2022, 'Chondroitin sulfate proteoglycans prevent immune cell phenotypic conversion and inflammation resolution via TLR4 in rodent models of spinal cord injury', Nature Communications, vol. 13, no. 1, pp. 2933. https://doi.org/10.1038/s41467-022-30467-5

Chondroitin sulfate proteoglycans prevent immune cell phenotypic conversion and inflammation resolution via TLR4 in rodent models of spinal cord injury. / Francos-Quijorna, Isaac; Sánchez-Petidier, Marina; Burnside, Emily R et al.
In: Nature Communications, Vol. 13, No. 1, 25.05.2022, p. 2933.

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

TY - JOUR

T1 - Chondroitin sulfate proteoglycans prevent immune cell phenotypic conversion and inflammation resolution via TLR4 in rodent models of spinal cord injury

AU - Francos-Quijorna, Isaac

AU - Sánchez-Petidier, Marina

AU - Burnside, Emily R

AU - Badea, Smaranda R

AU - Torres-Espin, Abel

AU - Marshall, Lucy

AU - de Winter, Fred

AU - Verhaagen, Joost

AU - Moreno-Manzano, Victoria

AU - Bradbury, Elizabeth J

PY - 2022/5/25

Y1 - 2022/5/25

N2 - 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.

AB - 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.

KW - Animals

KW - Chondroitin Sulfate Proteoglycans/metabolism

KW - Inflammation

KW - Rodentia

KW - Spinal Cord Injuries/pathology

KW - Toll-Like Receptor 4/genetics

U2 - 10.1038/s41467-022-30467-5

DO - 10.1038/s41467-022-30467-5

M3 - Article

C2 - 35614038

SN - 2041-1723

VL - 13

SP - 2933

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

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

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Keywords

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