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
N1 - © 2022. The Author(s).
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 -