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Extracellular cytochrome c as an intercellular signaling molecule regulating microglial functions
Ayden Gouveia1, Ekta Bajwa1, Andis Klegeris1
1Department of Biology, University of British Columbia Okanagan Campus, Canada.
Biochimica Et Biophysica Acta. General Subjects
|June 28, 2017
Summary
Extracellular cytochrome c acts as a signaling molecule, activating brain microglia via toll-like receptor 4 (TLR4) and JNK pathways. This finding suggests new therapeutic targets for brain diseases involving cell death and neuroinflammation.
Area of Science:
- Neuroimmunology
- Cellular Signaling
- Molecular Biology
Background:
- Cytochrome c is known for its role in apoptosis but also released extracellularly.
- The function of extracellular cytochrome c in the brain is not well understood.
- Microglia, brain immune cells, are activated by endogenous substances in various pathologies.
Purpose of the Study:
- To investigate the hypothesis that extracellular cytochrome c functions as an intercellular signaling molecule in the brain.
- To determine if brain microglia recognize and respond to extracellular cytochrome c.
- To elucidate the molecular mechanisms underlying cytochrome c-mediated microglial activation.
Main Methods:
- Utilized three cell types to model microglia.
- Measured respiratory burst activity, nitric oxide production, and cytotoxic secretions upon cytochrome c exposure.
- Investigated the involvement of toll-like receptor 4 (TLR4) and c-Jun N-terminal kinases (JNK) signaling pathways.
Main Results:
- Extracellular cytochrome c primed respiratory burst in HL-60 cells.
- Enhanced nitric oxide secretion by BV-2 cells and augmented cytotoxicity of THP-1 cells.
- Demonstrated that TLR4 and JNK pathways partially mediate these effects.
Conclusions:
- Extracellular cytochrome c interacts with microglia via TLR4, modulating their functions.
- Identified extracellular cytochrome c as a potential intercellular signal for microglial immune activation.
- Supported targeting TLR4 and JNK signaling for treating brain diseases with excessive cell death and microglial activation.
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