Extracellular cytochrome c as an intercellular signaling molecule regulating microglial functions
Autor: | Andis Klegeris, Ekta Bajwa, Ayden Gouveia |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Cytochrome Biophysics HL-60 Cells Biochemistry Interferon-gamma Mice 03 medical and health sciences medicine Extracellular Animals Humans Molecular Biology Cells Cultured Neuroinflammation Microglia biology Cytochrome c JNK Mitogen-Activated Protein Kinases Cytochromes c Cell biology Toll-Like Receptor 4 030104 developmental biology medicine.anatomical_structure Apoptosis biology.protein Apoptosome Signal transduction Signal Transduction |
Zdroj: | Biochimica et Biophysica Acta (BBA) - General Subjects. 1861:2274-2281 |
ISSN: | 0304-4165 |
Popis: | Background Cytochrome c is well known to be released from mitochondria into the cytosol where it can initiate apoptosis. Recent studies indicate that cytochrome c is also released into the extracellular space by both healthy and damaged cells, where its function is not well understood. We hypothesized that extracellular cytochrome c could function as an intercellular signaling molecule of the brain, which is recognized by brain microglia. These cells belong to the mononuclear phagocyte system and can be activated by endogenous substances associated with diverse pathologies including trauma, ischemic damage and neurodegenerative diseases. Methods Three different cell types were used to model microglia. Respiratory burst activity, nitric oxide production and cytotoxic secretions were measured following exposure of microglial cells to cytochrome c . Results We showed that extracellular cytochrome c primed the respiratory burst response of differentiated HL-60 cells, enhanced nitric oxide secretion by BV-2 cells, and augmented cytotoxicity of differentiated THP-1 cells. We demonstrated that the effects of cytochrome c on microglia-like cells were at least partially mediated by the toll-like receptor 4 (TLR4) and c-Jun N-terminal kinases (JNK) signaling pathway. Conclusions Extracellular cytochrome c can interact with microglia TLR4 and modulate select functions of these brain immune cells. General significance Our data identifies extracellular cytochrome c as a potential intercellular signaling molecule, which may be recognized by microglia causing or enhancing their immune activation. The data obtained support targeting TLR4 and JNK signaling as potential treatment strategies for brain diseases characterized by excessive cellular death and activation of microglia. |
Databáze: | OpenAIRE |
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