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.
Highlights
A well-controlled immune response is beneficial to maintaining central nervous system (CNS) homeostasis
Time course studies showed that 1,000 ng/ml High mobility group box 1 (HMGB1) significantly up-regulated mRNA expression levels of IL-1β and IL-6, and peaked at 4 h (Fig. 1d–e), while the increase of TNF-α reached the peak at 24 h and presented a biphasic pattern (Fig. 1f)
We demonstrated that HMGB1 could induce the expression of Regnase-1 in microglia both in vitro and in vivo
Summary
A well-controlled immune response is beneficial to maintaining central nervous system (CNS) homeostasis. HMGB1 binds to pattern recognition receptors on immune cells and triggers the intracellular signal cascades, resulting in a robust inflammatory response[9]. The binding of HMGB1 to its receptors recruits myeloid differentiation factor 88 to activate mitogen activated protein kinase (MAPK); subsequently, it induces nuclear factor-κ B (NF-κ B) to start the transcription of inflammatory cytokines, which leads to brain cell damage[15,18,19]. Suppression of Regnase-1 by microRNA(miR)-9 enhances inflammatory response in microglia[32] These findings collectively suggest that Regnase-1 can be induced by inflammatory milieu and functions as a regulatory factor to ameliorate neuroinflammatory injury in CNS. Knockdown of Regnase-1 in microglia enhanced transcription of IL-1β , IL-6 and exacerbated HMGB1-mediated inflammatory injury to neurons
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
