| First Author | Wenzel TJ | Year | 2019 |
| Journal | Biochim Biophys Acta Gen Subj | Volume | 1863 |
| Issue | 11 | Pages | 129400 |
| PubMed ID | 31344401 | Mgi Jnum | J:279256 |
| Mgi Id | MGI:6360415 | Doi | 10.1016/j.bbagen.2019.07.009 |
| Citation | Wenzel TJ, et al. (2019) Cytochrome c can be released into extracellular space and modulate functions of human astrocytes in a toll-like receptor 4-dependent manner. Biochim Biophys Acta Gen Subj 1863(11):129400 |
| abstractText | BACKGROUND: Chronic activation of glial cells contributes to neurodegenerative diseases. Cytochrome c (CytC) is a soluble mitochondrial protein that can act as a damage-associated molecular pattern (DAMP) when released into the extracellular space from damaged cells. CytC causes immune activation of microglia in a toll-like receptor (TLR) 4-dependent manner. The effects of extracellular CytC on astrocytes are unknown. Astrocytes, which are the most abundant glial cell type in the brain, express TLR 4 and secrete inflammatory mediators; therefore, we hypothesized that extracellular CytC can interact with the TLR 4 of astrocytes inducing their release of inflammatory molecules and cytotoxins. METHOD: Experiments were conducted using primary human astrocytes, U118 MG human astrocytic cells, BV-2 murine microglia, and SH-SY5Y human neuronal cells. RESULTS: Extracellularly applied CytC increased the secretion of interleukin (IL)-1beta, granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-12 p70 by cultured primary human astrocytes. Anti-TLR 4 antibodies blocked the CytC-induced secretion of IL-1beta and GM-CSF by astrocytes. Supernatants from CytC-activated astrocytes were toxic to human SH-SY5Y neuronal cells. We also demonstrated CytC release from damaged glial cells by measuring CytC in the supernatants of BV-2 microglia after their exposure to cytotoxic concentrations of staurosporine, amyloid-beta peptides (Abeta42) and tumor necrosis factor-alpha. CONCLUSION: CytC can be released into the extracellular space from damaged glial cells causing immune activation of astrocytes in a TLR 4-dependent manner. GENERAL SIGNIFICANCE: Astrocyte activation by CytC may contribute to neuroinflammation and neuronal death in neurodegenerative diseases. Astrocyte TLR 4 could be a potential therapeutic target in these diseases. |
