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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.

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. Here, 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. RESULTS:Following SCI, CRID3 administration inhibited inflammasome-related ASC and caspase-1, IL-1?, 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 have also been found. CONCLUSIONS:CRID3 may ameliorate 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.

SUBMITTER: Chen YQ

PROVIDER: S-EPMC7456508 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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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.

Chen Yu-Qing YQ Wang Sai-Nan SN Shi Yu-Jiao YJ Chen Jing J Ding Shu-Qin SQ Tang Jie J Shen Lin L Wang Rui R Ding Hai H Hu Jian-Guo JG Lü He-Zuo HZ

Journal of neuroinflammation 20200829 1

<h4>Background</h4>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. Here, CR ...[more]

PMID: 32861243

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Project description:Summary: We build a model for the molecular and cellular events underlying phenotypic discordance in glycine receptor defects (beta subunit). Some mice progress and die, while their littermates recover and get better, despite the same mutation on an inbred genetic background. We find evidence for glycine neurotransmitter toxicity and loss of glycinergic interneurons early in the disease, but some mice are able to keep things going until they can over-express homomeric alpha1 channels, whereupon they recover. In the mice progressing towards lethality, neurotransmitter toxicity too quickly extends to GABAergic interneurons and motorneurons, and they lose their window of time to upregulate the alpha1 glycine receptor, and they crash and burn. Importantly, human patients with glycine receptor defects typically show a resolution of their phenotype with age, and we propose that the same remodeling events are occuring in human patients. Hypothesis: Our data suggests that functional recovery of GlyRb mutant mice is likely due to expression of homomeric glycine receptors, rescue from excitotoxicity, and subsequent neuronal remodeling. We propose that human patients with hyperekplexia (mutations of glycine receptors) show remodeling similar to that of the recovering spastic mice, as human patients also show a lessening of symptoms as a function of age. Specific Aim: Murine models for human Startle Disease show clinical variability between littermates. Here, we determined the molecular remodeling of spastic GlyRb mutant spinal cord through the course of the disease, and develop a model for clinical disparity between littermates. At young ages, all animals were spastic, showed loss of glycine receptors, increased expression of vesicular glycine/GABA transporter and NMDA receptors, induction of activated caspase3, and preferential loss of glycinergic interneurons consistent with neurotransmitter toxicity model. Those littermates that recovered from symptoms showed strong over-expression of the GlyRa1 subunit, and increased myelination and synaptic plasticity. Littermates that showed a deteriorating clinical course failed to over-express GlyRa1, and also showed relative loss of gephyrin. These molecular changes were associated with preferential loss of GABAergic interneurons, and extensive motorneuron loss. Keywords: other

Dataset Information

CRID3, a blocker of apoptosis associated speck like protein containing a card, ameliorates murine spinal cord injury by improving local immune microenvironment.

Publications

CRID3, a blocker of apoptosis associated speck like protein containing a card, ameliorates murine spinal cord injury by improving local immune microenvironment.

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