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Published on: August 15, 2012
Regnase-1 in microglia negatively regulates high mobility group box 1-mediated inflammation and neuronal injury
Xiao-Xi Liu1, Chen Wang1,2, Shao-Fei Huang1
1Department of Neurology, Nanfang Hospital, Southern Medical University. Guangzhou, Guangdong 510515, P. R. China.
Abstract:
Extracellular high mobility group box 1 (HMGB1) has been demonstrated to function as a proinflammatory cytokine and induces neuronal injury in response to various pathological stimuli in central nervous system (CNS). However, the regulatory factor involved in HMGB1-mediated inflammatory signaling is largely unclear. Regulatory RNase 1 (Regnase-1) is a potent anti-inflammation enzyme that can degrade a set of mRNAs encoding proinflammatory cytokines. The present study aims to determine the role of Regnase-1 in the regulation of HMGB1-mediated inflammatory injury in CNS. Cultured microglia and rat brain were treated with recombinant HMGB1 to examine the induction of Regnase-1 expression. Moreover, the role of Regnase-1 in modulating the expression of inflammatory cytokines and neuronal injury was then investigated in microglia by specific siRNA knockdown upon HMGB1 treatment. Results showed that HMGB1 could significantly induce the de novo synthesis of Regnase-1 in cultured microglia. Consistently, Regnase-1 was elevated and found to be co-localized with microglia marker in the brain of rat treated with HMGB1. Silencing Regnase-1 in microglia enhanced HMGB1-induced expression of proinflammatory cytokines and exacerbated neuronal toxicity. Collectively, these results suggest that Regnase-1 can be induced by HMGB1 in microglia and negatively regulates HMGB1-mediated neuroinflammation and neuronal toxicity.
Insights
Regulatory RNase 1 (Regnase-1) counteracts inflammation caused by high mobility group box 1 (HMGB1) in the central nervous system. Regnase-1 induction by HMGB1 protects against neuroinflammation and neuronal injury.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Extracellular high mobility group box 1 (HMGB1) acts as a pro-inflammatory cytokine, contributing to neuronal injury in the central nervous system (CNS).
- The specific regulatory factors governing HMGB1-mediated inflammatory signaling in the CNS remain largely undefined.
- Regulatory RNase 1 (Regnase-1) is recognized as a key anti-inflammatory enzyme capable of degrading messenger RNAs (mRNAs) for pro-inflammatory cytokines.
Purpose of the Study:
- To elucidate the role of Regnase-1 in the regulation of HMGB1-induced inflammatory injury within the CNS.
- To investigate whether HMGB1 influences Regnase-1 expression in microglia and brain tissue.
- To determine the impact of Regnase-1 on the expression of inflammatory cytokines and neuronal toxicity in response to HMGB1.
Main Methods:
- Recombinant HMGB1 was used to treat cultured microglia and rat brain tissue to assess Regnase-1 expression.
- Specific small interfering RNA (siRNA) was employed to knockdown Regnase-1 in microglia under HMGB1 treatment.
- The expression levels of pro-inflammatory cytokines and the extent of neuronal toxicity were evaluated.
Main Results:
- HMGB1 significantly induced the de novo synthesis of Regnase-1 in cultured microglia.
- Regnase-1 levels were elevated and co-localized with microglia markers in HMGB1-treated rat brains.
- Silencing Regnase-1 amplified HMGB1-induced pro-inflammatory cytokine expression and worsened neuronal toxicity.
Conclusions:
- Regnase-1 is induced by HMGB1 in microglia within the CNS.
- Regnase-1 acts as a negative regulator of HMGB1-mediated neuroinflammation.
- Regnase-1 plays a protective role against HMGB1-induced neuronal toxicity.
