Perturbing chondroitin sulfate proteoglycan signaling through LAR and PTPσ receptors promotes a beneficial inflammatory response following spinal cord injury

Journal of Neuroinflammation, 2018 · DOI: https://doi.org/10.1186/s12974-018-1128-2 · Published: April 2, 2018

Simple Explanation

Traumatic spinal cord injury (SCI) results in upregulation of chondroitin sulfate proteoglycans (CSPGs) by reactive glia that impedes repair and regeneration in the spinal cord. The recent discovery of CSPG-specific receptors, leukocyte common antigen-related (LAR) and protein tyrosine phosphatase-sigma (PTPσ), allows unraveling the cellular and molecular mechanisms of CSPGs in SCI. We have unveiled a novel role for LAR and PTPσ in regulating neuroinflammation in traumatic SCI.

Study Duration

1-28 days post-SCI

Participants

112 adult female Sprague Dawley rats, 6 C75BL/6 mice, and 44 postnatal (P1–P3) SD pups

Evidence Level

Not specified

Key Findings

1
Blocking LAR and PTPσ reduces the population of classically activated M1 microglia/macrophages, while promoting alternatively activated M2 microglia/macrophages and T regulatory cells.
2
Inhibiting LAR and PTPσ in M1 and M2 microglia positively modulates their inflammatory response in the presence of CSPGs, and harnesses their ability for phagocytosis and mobilization.
3
CSPGs regulate microglia, at least in part, through the activation of the Rho/ROCK pathway downstream of LAR and PTPσ.

Research Summary

This study identifies inhibitory mechanisms for CSPGs and their receptors, LAR and PTPσ, in modulating the immune response after SCI. Modulation of CSPG signaling with ILP and ISP treatment drives an anti-inflammatory and pro-regenerative immune response, characterized by increased M2 microglia/macrophages and T regulatory cells. LAR and PTPσ signaling appears to regulate microglia by activating the RhoA/ROCK pathway, uncovering a key role in neuroinflammation after SCI.

Practical Implications

Immunotherapy for SCI

Targeting LAR and PTPσ represents a potential immunotherapy strategy for SCI.

Promoting M2 Microglia

Disruption of LAR and PTPσ signaling promotes M2 macrophages and increases pro-regenerative immune mediators.

Rho/ROCK Pathway Modulation

LAR and PTPσ signaling regulates microglia by activating the RhoA/ROCK pathway, providing a target for intervention.

Study Limitations

1
The CSPG-induced increase in nitrite production was not attenuated by ILP/ISP, suggesting other mechanisms are involved.
2
ILP/ISP therapy may have influenced interaction of LAR and PTPσ with other ligands beyond CSPGs.
3
Further elucidation is needed regarding the specific mechanisms through which CSPGs regulate nitrite production in M1 microglia.

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