Chondroitin Sulfate Proteoglycans Revisited: Its Mechanism of Generation and Action for Spinal Cord Injury

Aging and Disease, 2024 · DOI: http://dx.doi.org/10.14336/AD.2023.0512 · Published: February 1, 2024

Simple Explanation

After a spinal cord injury (SCI), specific brain cells called reactive astrocytes produce a substance known as chondroitin sulfate proteoglycans (CSPGs). These CSPGs can prevent nerve fibers from regrowing. New research has revealed that extracellular traps (ETs), released by immune cells after SCI, stimulate astrocytes to produce CSPGs. These CSPGs not only inhibit nerve regeneration but also affect inflammation and cell behavior. This review summarizes how ETs activate astrocytes to produce CSPGs, and it also discusses the various roles of CSPGs, including their impact on inflammation, cell movement, and cell specialization after SCI. The review suggests potential new targets for therapies aimed at reducing the negative effects of CSPGs.

Study Duration

Not specified

Participants

Not specified

Evidence Level

Review

Key Findings

1
Extracellular traps (ETs) released by neutrophils and microglia after SCI activate astrocytes to produce CSPGs, which inhibit axon regeneration.
2
CSPGs regulate inflammation and cell migration/differentiation after SCI, with both beneficial and harmful effects depending on the context and timing.
3
The inhibitory effects of CSPGs on axon regeneration are mediated through the Rho/ROCK pathway, impacting microtubule dynamics, mitochondrial transport, and autophagy flux.

Research Summary

This review discusses the generation and action mechanisms of CSPGs for the recovery of SCI. It highlights the role of extracellular traps (ETs) in stimulating astrocytes to produce CSPGs and the various intracellular signal transduction processes involved. The review explores the roles of CSPGs in inhibiting axon regeneration, regulating inflammation, and regulating cell migration and differentiation. It emphasizes that CSPGs can have different or even opposite effects at different SCI time points. Based on the mechanisms of CSPGs formation and action, the review proposes therapeutic strategies targeting histone deacetylase 6 (HDAC6), ETs, RAs, receptors, and enzymes. It also discusses future research directions and treatment strategies based on the mechanism of CSPGs after SCI.

Practical Implications

Targeting ET Formation

Inhibiting ET formation, particularly in aseptic inflammation scenarios like SCI, could alleviate inflammation and promote healing. PAD4 inhibitors and DNase1 are potential therapeutic agents.

Modulating CSPG Receptors

Targeted blocking of CSPG receptors, as opposed to complete digestion of CSPGs, can reduce inflammation, weaken the axon regeneration-blocking effects of CSPGs, and avoid the spread of inflammation.

Inhibiting HDAC6

Inhibition of HDAC6, a key regulator of axonal autophagic flux and mitochondrial transport, presents a potential therapeutic target for promoting axon regeneration after SCI.

Study Limitations

1
The exact mechanisms of NETs formation in SCI have not been fully understood yet.
2
The formation mechanism and role of MiETs have not been discovered yet, which could be important in SCI studies.
3
The standard classification of astrocytes has not been determined yet.

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