• Genomics & Informatics
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• 제21권1호
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• pp.2.1-2.14
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• 2023

Microglia, similar to peripheral macrophages, are the primary immune cells of the central nervous system (CNS). Microglia exist in the resting state in the healthy CNS, but can be activated and polarized into either M1 or M2 subtypes for immune defense and the maintenance of CNS homeostasis by multiple stimuli. Several long noncoding RNAs (lncRNAs) mediate human inflammatory diseases and neuropathologies by regulating their target genes. However, the function of common lncRNAs that contribute to microglial activation remains unclear. Thus, we used bioinformatic approaches to identify common lncRNAs involved in microglial activation in vitro. Our study identified several lncRNAs as common regulators of microglial activation. We identified 283 common mRNAs and 53 common lncRNAs during mouse M1 microglial activation processes, whereas 26 common mRNAs and five common lncRNAs were identified during mouse M2 microglial activation processes. A total of 648 common mRNAs and 274 common lncRNAs were identified during the activation of human M1 microglia. In addition, we identified 1,920 common co-expressed pairs in mouse M1 activation processes and 25 common co-expressed pairs in mouse M2 activation processes. Our study provides a comprehensive understanding of common lncRNA expression profiles in microglial activation processes in vitro. The list of common lncRNAs identified in this study provides novel evidence and clues regarding the molecular mechanisms underlying microglial activation.

• Molecules and Cells
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• 제40권3호
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• pp.163-168
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• 2017

Microglia are the primary resident immune cells of the central nervous system (CNS). They are the first line of defense of the brain's innate immune response against infection, injury, and diseases. Microglia respond to extracellular signals and engulf unwanted neuronal debris by phagocytosis, thereby maintaining normal cellular homeostasis in the CNS. Pathological stimuli such as neuronal injury induce transformation and activation of resting microglia with ramified morphology into a motile amoeboid form and activated microglia chemotax toward lesion site. This review outlines the current research on microglial activation and chemotaxis.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 2007년도 Proceedings of The Convention of The Korean Society of Applied Pharmacology
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• pp.15-22
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• 2007

Increasing evidence indicates that microglia-driven chronic inflammatory responses playa pathological role in the central nervous system. Activation of microglia is pivotal in the initiation and progression of neuroinflammation. Inhibition of the microglial activation may provide an effective therapeutic intervention that alleviates the progression of the neurodegenerative diseases. Anti-inflammatory agents may be a useful candidate for such a therapeutic approach. Continual investigation of the mechanisms underlying microglial activation and regulation of neuroinflammation by endogenous or exogenous factors would not only lead to the discovery of novel neuroprotective agents, but also help to understand complex pathophysiology of neurodegenerative diseases.

• BMB Reports
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• 제42권6호
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• pp.380-386
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• 2009

In neurodegenerative diseases, such as Alzheimer' and Parkinson', microglial cell activation is thought to contribute to CNS injury by producing neurotoxic compounds. Prothrombin and kringle-2 increase levels of NO and the mRNA expression of iNOS, IL-1$\beta$, and TNF-$\alpha$ in microglial cells. In contrast, the human prothrombin kringle-2 derived peptide NSA9 inhibits NO release and the production of pro-inflammatory cytokines such as IL-1$\beta$, TNF-$\alpha$, and IL-6 in LPS-activated EOC2 microglia. In this study, we investigated the anti-inflammatory effects of NSA9 in human prothrombin- and kringle-2-stimulated EOC2 microglia. Treatment with 20-100 ${\mu}M$ of NSA9 attenuated both prothrombin- and kringle-2-induced microglial activation. NO production induced by MAPKs and NF-$\kappa$B was similarly reduced by inhibitors of ERK (PD98059), p38 (SB203580), NF-$\kappa$B (N-acetylcysteine), and NSA9. These results suggest that NSA9 acts independently as an inhibitor of microglial activation and that its effects in EOC2 microglia are not influenced by the presence of kringle-2.

• Biomolecules & Therapeutics
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• 제21권1호
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• pp.21-28
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• 2013

Microglia play a role in maintaining and resolving brain tissue homeostasis. In pathological conditions, microglia release pro-inflammatory cytokines and cytotoxic factors, which aggravate the progression of neurodegenerative diseases. Autophagy pathway might be involved in the production of pro-inflammatory cytokines and cytotoxic factors in microglia, though details of the mechanism remain largely unknown. In the present study, we examined the role of the autophagy pathway in activated BV2 microglia cells. In BV2 cells, rapamycin treatment activated the formation of anti-LC3-labeled autophagosomes, whereas the ATG5 depletion using siRNA-ATG5 prevented the formation of LC3-labeled autophagosomes, indicating that BV2 cells exhibit an active classical autophagy system. When treated with LPS, BV2 cells expressed an increase of anti-LC3-labeled dots. The levels of LC3-labeled dots were not suppressed, instead tended to be enhanced, by the inhibition of the autophagy pathway with siRNA-ATG5 or wortmannin, suggesting that LPS-induced LC3-labeled dots in nature were distinct from the typical autophagosomes. The levels of LPS-induced expression of iNOS and IL6 were suppressed by treatment with rapamycin, and conversely, their expressions were enhanced by siRNA-ATG5 treatment. Moreover, the activation of the autophagy pathway using rapamycin inhibited cell death of LPS-stimulated microglia. These results suggest that although microglia possess a typical autophagy pathway, the glial cells express a non-typical autophagy pathway in response to LPS, and the activation of the autophagy pathway suppresses the expression of iNOS and IL6, and the cell death of LPS-stimulated microglia.

• Korean Journal of Acupuncture
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• 제36권4호
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• pp.264-273
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• 2019

Objectives : Microglia play a crucial role in electroacupuncture (EA) analgesia on neuropathic pain. The role of chemokines in producing analgesic effects of EA, however, is largely unknown. In the present study, we investigated the role of chemokines in producing analgesic effects of EA in the neuropathic pain model. Methods : Sprague-Dawley rats were randomly assigned into three groups (anesthetized group (ANE), non-acupoint EA group (NAP), and ST36 - GB34 EA group (ACU)). Neuropathic pain was induced by tight ligation of L5 spinal nerve. Mechanical and thermal hypersensitivity of hind paw was tested. Western blot tests and immunofluorescence assay for C-C motif chemokine ligand 2 (CCL2) levels and microglia activation were performed on spinal cord L5/6. EA was treated once daily from the 3rd day after surgery for 5 days. Results : EA treatments applied to ST36 and GB34 significantly reduced both mechanical and thermal hypersensitivity after two and three times of treatment, respectively. While CCL2 expression significantly increased in neuropathic rats, it was significantly reduced in the ACU. In addition, co-localization of CCL2 and activated microglia significantly decreased in the ACU compared to those of ANE and NAP in the spinal cord L5/L6 dorsal horn. Conclusions : The present results suggest that EA applied to ST36 and GB34 modulates the reduction of CCL2 release from the injured neurons and consequently decreases microglia activation in the spinal cord. Regulation of chemokine induced spinal activation of microglia plays a key role in analgesic effects of EA in the rat model of neuropathic pain.

• 약학회지
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• 제44권5호
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• pp.448-454
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• 2000

Microglia, brain resident macrophages, play a central role in the inflammatory responses of the brain and are activated in brain injuries and several neurodegenerative diseases such as Alzheimer's and Parkinson's disease, thereby aggravating the course of these diseases. In this study, the effects of plantderived compounds such as curcumin or gingerol on the microglial activation were examined. Microglial cultures were prepared from 2~3 week mixed primary glial cultures obtained from the cerebral cortex of 1~2 day old rats and identified by immunocytochemistry using microglial-specific antibody OX-42. Microglia were activated by lipopolysaccharide (LPS) and interferon-${\gamma}$ (IFN-${\gamma}$) and the effect of curcumin or 6-gingerol on the microglial activation was examined. Specific parameters measured to monitor microglial activation were nitric oxide (NO), prostaglandin E$_2$(PGE$_2$) and tumor necrosis factor-$\alpha$ (TNF-$\alpha$) release. Curcumin (1~10 $\mu$M) inhibited NO release induced by LPS and IFN-${\gamma}$ in a dose-dependent manner whereas 6-gingerol (2~20 $\mu$M) did not have any effect on LPS/IFN-${\gamma}$-induced NO release. The levels of PGE$_2$and TNF-$\alpha$ induced by LPS and IFN-${\gamma}$ were also inhibited by 1~10 $\mu$M curcumin in a dose-dependent manner. These results showed that curcumin could modulate microglial activation.

• The Korean Journal of Pain
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• 제34권1호
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• pp.47-57
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• 2021

Background: Lumbar disc herniation (LDH) is a common cause of radicular pain, but the mechanism is not clear. In this study, we investigated the engagement of toll-like receptor 4 (TLR4) and the nuclear factor-kappa B (NF-κB) in radicular pain and its possible mechanisms. Methods: An LDH model was induced by autologous nucleus pulposus (NP) implantation, which was obtained from coccygeal vertebra, then relocated in the lumbar 4/5 spinal nerve roots of rats. Mechanical and thermal pain behaviors were assessed by using von Frey filaments and hotplate test respectively. The protein level of TLR4 and phosphorylated-p65 (p-p65) was evaluated by western blotting analysis and immunofluorescence staining. Spinal microglia activation was evaluated by immunofluorescence staining of specific relevant markers. The expression of proand anti-inflammatory cytokines in the spinal dorsal horn was measured by enzyme linked immunosorbent assay. Results: Spinal expression of TLR4 and p-NF-κB (p-p65) was significantly increased after NP implantation, lasting up to 14 days. TLR4 was mainly expressed in spinal microglia, but not astrocytes or neurons. TLR4 antagonist TAK242 decreased spinal expression of p-p65. TAK242 or NF-κB inhibitor pyrrolidinedithiocarbamic acid alleviated mechanical and thermal pain behaviors, inhibited spinal microglia activation, moderated spinal inflammatory response manifested by decreasing interleukin (IL)-1β, IL-6, tumor necrosis factor-α expression and increasing IL-10 expression in the spinal dorsal horn. Conclusions: The study revealed that TLR4/NF-κB pathway participated in radicular pain by encouraging spinal microglia activation and inflammatory response.

• The Korean Journal of Physiology and Pharmacology
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• 제18권5호
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• pp.397-402
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• 2014

Microglia are activated by inflammatory and pathophysiological stimuli in neurodegenerative diseases, and activated microglia induce neuronal damage by releasing cytotoxic factors like nitric oxide (NO). Activated microglia synthesize a significant amount of vitamin $D_3$ in the rat brain, and vitamin $D_3$ has an inhibitory effect on activated microglia. To investigate the possible role of vitamin $D_3$ as a negative regulator of activated microglia, we examined the effect of 25-hydroxyvitamin $D_3$ on NO production of lipopolysaccharide (LPS)-stimulated microglia. Treatment with LPS increased the production of NO in primary cultured and BV2 microglial cells. Treatment with 25-hydroxyvitamin $D_3$ inhibited the generation of NO in LPS-activated primary microglia and BV2 cells. In addition to NO production, expression of 1-${\alpha}$-hydroxylase and the vitamin D receptor (VDR) was also upregulated in LPS-stimulated primary and BV2 microglia. When BV2 cells were transfected with 1-${\alpha}$-hydroxylase siRNA or VDR siRNA, the inhibitory effect of 25-hydroxyvitamin $D_3$ on activated BV2 cells was suppressed. 25-Hydroxyvitamin $D_3$ also inhibited the increased phosphorylation of p38 seen in LPS-activated BV2 cells, and this inhibition was blocked by VDR siRNA. The present study shows that 25-hydroxyvitamin $D_3$ inhibits NO production in LPS-activated microglia through the mediation of LPS-induced 1-${\alpha}$-hydroxylase. This study also shows that the inhibitory effect of 25-hydroxyvitamin $D_3$ on NO production might be exerted by inhibiting LPS-induced phosphorylation of p38 through the mediation of VDR signaling. These results suggest that vitamin $D_3$ might have an important role in the negative regulation of microglial activation.

• Mass Spectrometry Letters
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• 제5권3호
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• pp.70-78
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• 2014

Microglia are the confined immune cells of the central nervous system (CNS). In response to injury or infection, microglia readily become activated and release proinflammatory mediators that are believed to contribute to microglia-mediated neurodegeneration. In the present study, inflammation was induced in the immortalized murine microglial cell line BV-2 by lipopolysaccharide (LPS) treatment. We firstly performed phosphoproteomics analysis and phosphoinositide lipidomics analysis with LPS activated microglia in order to compare phosphorylation patterns in active and inactive microglia and to detect the pattern of changes in phosphoinositide regulation upon activation of microglia. Mass spectrometry analysis of the phosphoproteome of the LPS treatment group compared to that of the untreated control group revealed a notable increase in the diversity of cellular phosphorylation upon LPS treatment. Additionally, a lipidomics analysis detected significant increases in the amounts of phosphoinositide species in the LPS treatment. This investigation could provide an insight for understanding molecular mechanisms underlying microglia-mediated neurodegenerative diseases.