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Anti-Inflammatory Effects of GPR55 Agonists and Antagonists in LPS-Treated BV2 Microglial Cells
Lu Sun1, Matthias Apweiler1, Claus Normann2
1Neuroimmunology and Neurochemistry Research Group, Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, D-79104 Freiburg, Germany.
Abstract:
Chronic inflammation is driven by proinflammatory cytokines such as interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and chemokines, such as c-c motif chemokine ligand 2 (CCL2), CCL3, C-X-C motif chemokine ligand 2 (CXCL2), and CXCL10. Inflammatory processes of the central nervous system (CNS) play an important role in the pathogenesis of various neurological and psychiatric disorders like Alzheimer's disease, Parkinson's disease, and depression. Therefore, identifying novel anti-inflammatory drugs may be beneficial for treating disorders with a neuroinflammatory background. The G-protein-coupled receptor 55 (GPR55) gained interest due to its role in inflammatory processes and possible involvement in different disorders. This study aims to identify the anti-inflammatory effects of the coumarin-based compound KIT C, acting as an antagonist with inverse agonistic activity at GPR55, in lipopolysaccharide (LPS)-stimulated BV2 microglial cells in comparison to the commercial GPR55 agonist O-1602 and antagonist ML-193. All compounds significantly suppressed IL-6, TNF-α, CCL2, CCL3, CXCL2, and CXCL10 expression and release in LPS-treated BV2 microglial cells. The anti-inflammatory effects of the compounds are partially explained by modulation of the phosphorylation of p38 mitogen-activated protein kinase (MAPK), p42/44 MAPK (ERK 1/2), protein kinase C (PKC) pathways, and the transcription factor nuclear factor (NF)-κB, respectively. Due to its potent anti-inflammatory properties, KIT C is a promising compound for further research and potential use in inflammatory-related disorders.
Insights
The novel compound KIT C demonstrates potent anti-inflammatory effects by reducing key cytokines and chemokines in microglial cells. This suggests KIT C
Area of Science:
- Neuroinflammation research
- Pharmacology of G-protein-coupled receptors
- Cytokine and chemokine signaling
Background:
- Chronic inflammation, driven by cytokines like IL-6 and TNF-α, contributes to neurological disorders.
- Central nervous system (CNS) inflammation is implicated in Alzheimer's, Parkinson's, and depression.
- G-protein-coupled receptor 55 (GPR55) is a potential target for modulating inflammatory processes.
Purpose of the Study:
- To investigate the anti-inflammatory effects of the GPR55 antagonist KIT C.
- To compare KIT C's effects with known GPR55 modulators (O-1602 and ML-193).
- To explore the underlying molecular mechanisms of KIT C's anti-inflammatory action.
Main Methods:
- Utilized lipopolysaccharide (LPS)-stimulated BV2 microglial cells.
- Administered KIT C, O-1602, and ML-193 to assess their impact on inflammatory markers.
- Analyzed the expression and release of cytokines (IL-6, TNF-α) and chemokines (CCL2, CCL3, CXCL2, CXCL10).
- Investigated the modulation of signaling pathways including p38 MAPK, ERK1/2, PKC, and NF-κB.
Main Results:
- All tested compounds, including KIT C, significantly suppressed the expression and release of IL-6, TNF-α, CCL2, CCL3, CXCL2, and CXCL10.
- KIT C exhibited potent anti-inflammatory properties in LPS-treated microglial cells.
- The anti-inflammatory effects were partly attributed to the modulation of p38 MAPK, ERK1/2, PKC, and NF-κB pathways.
Conclusions:
- KIT C demonstrates significant anti-inflammatory effects in a microglial cell model.
- KIT C's mechanism involves the modulation of key inflammatory signaling pathways.
- KIT C is a promising candidate for further investigation in neuroinflammatory disorders.
