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^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

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
Article number	2933
Pages (from-to)	1-23
Number of pages	23
Journal	Nature Communications
Volume	13
Early online date	25 May 2022
DOIs	https://doi.org/10.1038/s41467-022-30467-5
Publication status	Published - 2022

Bibliographical note

Publisher Copyright:
© 2022, The Author(s).

Funding

The work was supported by grants from the following organisations: the U.K. Medical Research Council (SNCF G1002055; ERA-NET NEURON MR/R005532/1) and the Rosetrees Trust (CF1\100006) to E.J.B.; the Fondo Europeo de Desarrollo Regional (FEDER)/Ministerio de Ciencia e Innovación—Agencia Estatal de Investigación “RTI2018-095872-B-C21/ERDF” (included in the FEDER programme for the Comunidad Valenciana 2014-2020) to V.M.M.; and Wings for Life Spinal Cord Research Foundation (WFL-UK-01/20 Project 214 to E.J.B.; WFL-NL-25/20 Project 238 to J.V.). We thank Dr. S. Akira (Osaka) and Dr C. Guerri for providing TLR4 mice. −/−

Funders	Funder number
Medical Research Council
Ministerio de Ciencia e Innovación
Comunidad Valenciana 2014-2020
European Regional Development Fund
SNCF	G1002055, ERA-NET NEURON MR/R005532/1
Agencia Estatal de Investigación	RTI2018-095872-B-C21
Rosetrees Trust	CF1\100006
UK Research and Innovation	MR/R005532/1
Wings for Life	WFL-UK-01/20

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-022-30467-5

Persistent URL (handle)

Persistent link

Cite this

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, 1-23. Article 2933. https://doi.org/10.1038/s41467-022-30467-5

@article{ffbac226f195417885d09975973f2b61,

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.",

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.\}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

doi = "10.1038/s41467-022-30467-5",

language = "English",

volume = "13",

pages = "1--23",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

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, 2933, pp. 1-23. 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, 2933, 2022, p. 1-23.

Research output: Contribution to Journal › Article › Academic › 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

Y1 - 2022

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.

UR - https://www.scopus.com/pages/publications/85130709423

UR - https://www.scopus.com/inward/citedby.url?scp=85130709423&partnerID=8YFLogxK

U2 - 10.1038/s41467-022-30467-5

DO - 10.1038/s41467-022-30467-5

M3 - Article

C2 - 35614038

AN - SCOPUS:85130709423

SN - 2041-1723

VL - 13

SP - 1

EP - 23

JO - Nature Communications

JF - Nature Communications

M1 - 2933

ER -

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

Abstract

Bibliographical note

Funding

UN SDGs

Access to Document

Persistent URL (handle)

Other files and links

Fingerprint

Cite this