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Cytochrome c can be released into extracellular space and modulate functions of human astrocytes in a toll-like

Tyler J Wenzel¹, Ekta Bajwa¹, Andis Klegeris¹

¹Department of Biology, University of British Columbia Okanagan Campus, Kelowna, British Columbia V1V 1V7, Canada.

Biochimica Et Biophysica Acta. General Subjects

|July 26, 2019

Abstract

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)-1β, 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-1β 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-β peptides (Aβ42) and tumor necrosis factor-α.

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.

Insights

Extracellular cytochrome c (CytC) from damaged glial cells activates astrocytes via toll-like receptor 4 (TLR4), promoting neuroinflammation. This astrocyte activation contributes to neuronal death in neurodegenerative diseases.

Area of Science:

Neuroscience
Immunology
Cell Biology

Background:

Chronic glial cell activation is implicated in neurodegenerative diseases.
Extracellular cytochrome c (CytC), a mitochondrial protein, acts as a damage-associated molecular pattern (DAMP).
CytC activates microglia via toll-like receptor 4 (TLR4); its effect on astrocytes is unknown.

Purpose of the Study:

To investigate the effects of extracellular CytC on astrocytes.
To determine if CytC-induced astrocyte activation involves TLR4.
To assess the impact of activated astrocytes on neuronal cells.

Main Methods:

Primary human astrocytes and astrocytic cell lines were treated with CytC.
TLR4 involvement was assessed using anti-TLR4 antibodies.
CytC release from damaged glial cells was measured.
Neuronal toxicity was evaluated using SH-SY5Y cells.

Main Results:

Extracellular CytC stimulated astrocytes to secrete inflammatory mediators like IL-1β and GM-CSF.
Anti-TLR4 antibodies inhibited CytC-induced IL-1β and GM-CSF secretion.
Supernatants from CytC-activated astrocytes exhibited toxicity towards neuronal cells.
CytC was released from glial cells damaged by cytotoxic agents.

Conclusions:

Extracellular CytC released from damaged glial cells activates astrocytes in a TLR4-dependent manner.
Astrocyte activation by CytC may contribute to neuroinflammation and neuronal death.
Astrocyte TLR4 represents a potential therapeutic target for neurodegenerative diseases.

Read full analysis

Keywords:

Cell death Cytokines Damage-associated molecular pattern (DAMP)Neuroinflammation Neurotoxicity TAK 242

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