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.

Small leucine-rich proteoglycans inhibit CNS regeneration by modifying the structural and mechanical properties of the lesion environment

“…Fibrous scar formation is considered to be a major factor in limiting axon regeneration in the adult mammalian CNS ( 2 ). Several scar components, such as myelin-associated factors, basal lamina components, and high molecular weight chondroitin sulfate proteoglycans (CSPGs), have been identified as inhibitors of axonal regrowth through mechanisms including growth cone collapse, repellence or entrapment, and prevention of inflammation resolution ( 3–5 ). However, removing these extracellular matrix (ECM) factors results in only modest regeneration, suggesting that critical molecules and mechanisms contributing to regeneration failure remain to be discovered ( 6–8 ).…”

Bridging the gap of axonal regeneration in the central nervous system: A state of the art review on central axonal regeneration

“…There is new evidence showing that they can regulate multiple aspects of the immune response in chronic inflammatory and demyelinating disorders of the CNS. In a new study by Francos-Quijorna et al (2022) , the molecular and cellular basis of these immunomodulatory effects of CSPGs were investigated. They showed that CSPGs impede the resolving phase of wound repair and that this results in the wound remaining in a chronic state.…”

“…It also promotes wound resolution by digesting CSPGs. This results in a bias of microglial phenotype from M1-like pro-inflammatory type to favor the M2-like phenotype which promotes wound healing ( Francos-Quijorna et al, 2022 ). Furthermore, axon outgrowth is further enhanced by targeting ChABC to the axonal compartment ( Day et al, 2020 ).…”

“…These results are very encouraging however, it is of note here that it is likely that the presence/levels of CSPGs could significantly influence the outcome since it has been shown that even neonatal rat microglia convert from M2-like wound resolving to M1-like inflammatory phenotype in the presence of CSPGs. This would be predicted to delay wound resolution resulting in the wound remaining in a chronic state ( Francos-Quijorna et al, 2022 ).…”

Clickable Biomaterials for Modulating Neuroinflammation

“…In many contexts, the inflamed CNS experiences an ingress of bone marrow-derived monocytes, which differentiate into monocyte-derived macrophages and play a pleiotropic role in neuroinflammation [ 58 ]. Macrophage interactions with myelin debris and chondroitin sulfate proteoglycans in the glial scar induce the production of pro-inflammatory cytokines and reactive species that propagate neurotoxic inflammation [ 59 , 60 ]. Conversely, the presence of bone marrow-derived macrophages also mitigates microglial reactivity and ultimately reduces inflammation after CNS injury [ 61 , 62 ].…”