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CRID3, a Blocker of Apoptosis Associated Speck Like Protein Containing a Card, Ameliorates Murine Spinal Cord Injury by Improving Local Immune Microenvironment
36 Pages Posted: 25 Jun 2020
More...Abstract
Background: After spinal cord injury (SCI), destructive immune cell subsets are dominant in the local microenvironment, which are the important mechanism of injury. Studies have shown that inflammasomes play an important role in the inflammation following SCI, and apoptosis associated speck like protein containing a card (ASC) is the adaptor protein shared by inflammasomes. Therefore, we speculated that inhibiting ASC may improve the local microenvironment of injured spinal cord. In this study, CRID3, a blocker of ASC oligomerization, was used to study its effect on the local microenvironment and the possible role in neuroprotection following SCI.
Methods: Murine SCI model was created using an Infinite Horizon impactor at T9 vertebral level with a force of 50 Kdynes and CRID3 (50 mg/kg) was intraperitoneally injected following injury. ASC and its downstream molecules in inflammasome signaling pathway were measured by western blot. The immune cell subsets were detected by immunohistofluorescence (IHF) and flow cytometry (FCM). The spinal cord fibrosis area, neuron survival, myelin preservation and functional recovery were assessed.
Findings: Following SCI, CRID3 administration inhibited inflammasome-related ASC and caspase-1, IL-1β and IL-18 activation, which consequently suppressed M1 microglia, Th1 and Th1Th17 differentiation, and increased M2 microglia and Th2 differentiation. Accordingly, the improved histology and behavior also been found.
Interpretations: CRID3 may ameliorates murine SCI by inhibiting inflammasome activation, reducing proinflammatory factor production, restoring immune cell subset balance and improving local immune microenvironment, and early administration may be a promising therapeutic strategy for SCI.
Funding Statement: This study is supported by National Natural Science Foundation of China (81772321).
Declaration of Interests: The authors declare no competing financial interest.
Ethics Approval Statement: The study was approved by the Institutional Committee on Animal Care, Use and Research of the Bengbu Medical College.
Keywords: spinal cord injury; CRID3; inflammasome; apoptosis associated speck like protein containing a card; immune microenvironment; locomotor recovery
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