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Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity
Published on: January 7, 2019
Targeting HMGB1-TLR4 signaling by miR-216a-5p elevation alleviates the inflammatory behavioral hypersensitivity
Zhou Zhenzhen1, Liu Fenghao2, Ma Meina1
1Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou City, Hebei Province 061001, PR China.
Abstract:
Neuroinflammation induced by microglial activation has a critical role in inflammatory pain. In this study, we detected the function of miR-216a-5p in the progression of inflammatory behavioral hypersensitivity. Here, decreases of miR-216a-5p and up-regulation of high-mobility group box1 (HMGB1) were observed in complete freund's adjuvant (CFA)-induced inflammatory pain model in mice and LSP-activated BV2 microglia. HMGB1 was identified as a target of miR-216a-5p by luciferase reporter system. Ectopic expression of miR-216a-5p suppressed microglial marker IBA-1 expression and subsequent pro-inflammatory cytokine releases (IL-1β, IL-6 and TNF-α) from LPS-activated microglia. Additionally, LPS exposure enhanced the protein expression levels of HMGB1, TLR4 and p-p65 NF-kB in microglia, which were abrogated following miR-216a-5p overexpression. Intriguingly, transfection of HMGN1 cDNA into BV2 microglial cells reversed the inhibitory effects of miR-216a-5p elevation on microglial activation-triggered inflammatory response. Intrathecal delivery of LV-miR-216a-5-p ameliorated CFA-evoked mechanical and thermal hyperalgesia in mice. Concomitantly, overexpressing miR-216a-5p also restrained the inflammatory response and microglia activation in CFA-induced inflammatory mouse models, concomitant with the decreases in the expression of HMGB1, TLR4 and p-p65 NF-kB in spinal cord. Thus, these findings highlight that miR-216a-5p may alleviate inflammatory behavioral hypersensitivity by blocking microglia-mediated neuroinflammation via targeting the HMGB1-TLR4-NF-kB pathway, supporting miR-216a-5p as a potential therapeutic avenue for inflammatory pain.
Insights
MicroRNA-216a-5p (miR-216a-5p) alleviates inflammatory pain by suppressing microglial activation and neuroinflammation. It targets high-mobility group box 1 (HMGB1), reducing inflammatory responses and hypersensitivity.
Area of Science:
- Neuroscience
- Molecular Biology
- Immunology
Background:
- Neuroinflammation, driven by microglial activation, plays a key role in inflammatory pain.
- MicroRNAs (miRNAs) are emerging regulators of inflammatory processes.
Purpose of the Study:
- To investigate the role of miR-216a-5p in inflammatory pain.
- To elucidate the underlying molecular mechanisms of miR-216a-5p in microglial activation and pain hypersensitivity.
Main Methods:
- Utilized a complete Freund's adjuvant (CFA)-induced inflammatory pain mouse model.
- Employed LPS-activated BV2 microglia cell models.
- Performed luciferase reporter assays to identify miRNA targets.
- Assessed microglial activation markers (IBA-1), pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), and signaling pathways (HMGB1, TLR4, NF-κB).
- Investigated the therapeutic potential of intrathecal delivery of miR-216a-5p.
Main Results:
- Decreased miR-216a-5p and increased high-mobility group box 1 (HMGB1) were observed in inflammatory pain models.
- HMGB1 was confirmed as a direct target of miR-216a-5p.
- miR-216a-5p overexpression suppressed microglial activation, pro-inflammatory cytokine release, and the HMGB1-TLR4-NF-κB pathway.
- Intrathecal delivery of miR-216a-5p ameliorated CFA-induced hyperalgesia in mice.
Conclusions:
- miR-216a-5p exerts anti-inflammatory effects by inhibiting microglial activation.
- The mechanism involves targeting HMGB1 and subsequently modulating the TLR4-NF-κB pathway.
- miR-216a-5p represents a promising therapeutic target for managing inflammatory pain.
