Blockade of the ADAM8‑Fra‑1 complex attenuates neuroinflammation by suppressing the Map3k4/MAPKs axis after spinal cord injury

Cellular & Molecular Biology Letters, 2024 · DOI: https://doi.org/10.1186/s11658-024-00589-3 · Published: May 6, 2024

Simple Explanation

Mechanical spinal cord injury (SCI) leads to neuroinflammation and neuropathy. ADAM8, a metalloproteinase, might regulate neuroinflammation in microglia after SCI. In microglia stimulated by HMGB1, ADAM8 promotes inflammation, migration, and proliferation by interacting with ERKs and Fra-1, activating Map3k4/JNKs/p38. In SCI mice, BK-1361, an ADAM8 inhibitor, reduced neuroinflammation, microglial activation, glial scar formation, and preserved myelin and axonal structures, improving locomotor recovery.

Study Duration

Not specified

Participants

12 SCI patients, 12 control patients, Adult male C57BL/6J mice

Evidence Level

Level 2: Experimental Study

Key Findings

1
ADAM8 up-regulation in microglia is associated with inflammation after SCI.
2
ADAM8 forms a complex with ERK and Fra-1 to activate the Map3k4/JNK/p38 axis in microglia.
3
Inhibition of ADAM8 with BK-1361 decreases neuroinflammation, glial formation, and neurohistological loss, improving locomotor function in SCI mice.

Research Summary

This study investigates the role of ADAM8 in microglia-mediated neuroinflammation following spinal cord injury (SCI). The research demonstrates that ADAM8 promotes microglial activation, migration, and proliferation by forming a complex with ERK and Fra-1, activating the Map3k4/JNK/p38 axis. Inhibition of ADAM8 via BK-1361 reduces neuroinflammation, glial scar formation, and neurohistological damage, leading to improved locomotor function in SCI mice.

Practical Implications

Therapeutic Target

ADAM8 represents a potential therapeutic target for mitigating neuroinflammation and improving outcomes after spinal cord injury.

Pharmacological Intervention

BK-1361, an ADAM8 inhibitor, shows promise as a pharmacological intervention to reduce secondary neuropathies and promote locomotor function recovery post-SCI.

Microglia Modulation

Modulating microglial activity via ADAM8 inhibition could be a strategy to limit neuroinflammation and promote tissue preservation in SCI.

Study Limitations

1
The study did not identify whether ADAM8 promoted Fra-1 activation, which depended on ERK1/2 expression
2
The mechanism of ADAM8 action was only ascertained in microglia after SCI
3
The study did not use conditional ADAM8 knockout mouse, targeting microglia

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