Genetic Targeting of Protease Activated Receptor 2 Reduces Inflammatory Astrogliosis and Improves Recovery of Function after Spinal Cord Injury

Neurobiol Dis., 2015 · DOI: 10.1016/j.nbd.2015.08.021 · Published: November 1, 2015

Simple Explanation

Inflammatory astrogliosis, a condition where inflammation and scarring occur in the spinal cord, can worsen damage after an injury. This study found that a protein called Protease Activated Receptor 2 (PAR2) plays a key role in this process. Mice lacking the PAR2 gene showed better motor coordination and strength after a spinal cord injury compared to normal mice. These mice also had reduced levels of inflammation and scarring in their spinal cords. The researchers found that PAR2 affects a signaling pathway involving IL-6 and STAT3, which promotes inflammation and scarring. Blocking PAR2 could be a new way to improve recovery after spinal cord injuries.

Study Duration

30 days

Participants

Adult female PAR2+/+ or PAR2−/− mice

Evidence Level

Not specified

Key Findings

1
Mice lacking the PAR2 gene showed greater improvements in motor coordination and strength after spinal cord injury compared to wild type littermates.
2
SCI in PAR2−/− mice was accompanied by improved preservation of protein kinase C gamma (PKCγ)-immunopositive corticospinal axons
3
Data point to a signaling circuit in primary astrocytes in which neurosin signaling at PAR2 promotes IL-6 secretion and canonical STAT3 signaling.

Research Summary

This study investigates the role of Protease Activated Receptor 2 (PAR2) in inflammatory astrogliosis following spinal cord injury (SCI). The results demonstrate that mice lacking the PAR2 gene exhibit improved motor recovery and reduced inflammation and astrogliosis after SCI. The study identifies a signaling pathway involving PAR2, IL-6, and STAT3 in astrocytes that promotes inflammatory astrogliosis, suggesting PAR2 as a potential therapeutic target for SCI.

Practical Implications

Therapeutic Target

PAR2 and its agonists represent potential drug targets to foster neuromotor recovery after SCI.

Limit Inflammation

Targeting PAR2 signaling globally may prove useful to limit trauma-induced astrogliosis, to constrain pro-inflammatory cytokine production and apoptosis, and to protect sparred axons.

Clinical Translation

Further research is needed to determine whether PAR2-inhibitors, applied at select time points after injury, replicate or enhance the improvements in functional outcomes observed in PAR2 gene deletion.

Study Limitations

1
Additional studies using cell specific PAR2−/− knockdown strategies will be needed to address whether the reductions in pro-inflammatory cytokines and astrogliosis and the improved functional status of corticospinal axons observed in PAR2−/− mice may occur by direct or indirect means
2
Future studies are needed to define the range of cells expressing PAR2 in SCI and to determine essential mechanisms involved by selective targeting of PAR2 in different cell types.
3
It will be necessary to determine whether PAR2-inhibitors, applied at select time points after injury, replicate or enhance the improvements in functional outcomes observed here in the case of global PAR2 gene deletion.

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