4.5 Article

Extracellular cytochrome c as an intercellular signaling molecule regulating microglial functions

期刊

BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
卷 1861, 期 9, 页码 2274-2281

出版社

ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbagen.2017.06.017

关键词

Microglia; DAMPs; Cytochrome c; Mitochondrial proteins; Mononuclear phagocytes; Neuroinflammation; Neurotoxicity

资金

  1. Natural Sciences and Engineering Research Council of Canada (NSERC)
  2. Jack Brown and Family Alzheimer's Disease Research Foundation
  3. UBC Okanagan Campus

向作者/读者索取更多资源

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.

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