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Monitoring Astrocyte Reactivity and Proliferation in Vitro Under Ischemic-Like Conditions
Published on: October 21, 2017
Role of IDO activation in anti-microbial defense in human native astrocytes
Claudia Oberdörfer1, Ortwin Adams, Colin R MacKenzie
1Institut für Medizinische Mikrobiologie und Virologie, Heinrich-Heine-Universität, Universitätsstrasse 1, Geb. 22.21, 40225 Düsseldorf, Germany.
Abstract:
The most serious complication of human toxoplasmosis is the development of toxoplasmic encephalitis. It is well established that in the brain Toxoplasma gondii is able to replicate in microglial cells, astrocytes and neurons, and that all three cell types can harbor toxoplasma cysts. The role of astrocytes in the defense against toxoplasma is not clear. The most prominent effector-mechanisms against toxoplasma are the induction of the inducible form of the nitric oxide synthase (iNOS), and the induction of indoleamine 2,3-dioxygenase (IDO). In this paper we show that interferon (IFN)-gamma-activated, native human astrocytes express IDO activity, as shown by the detection of IDO mRNA using RT-PCR, detection of enzyme expression with IDO-specific monoclonal antibodies in Western blots, as well as by direct measurement of enzyme activity in the activated cells. IFN-gamma-mediated IDO activity in human astrocytes inhibits the growth of Toxoplasma gondii and of group B streptococci. Furthermore, we show for the first time that IFN-gamma induced IDO activity is also effective in inhibiting the growth of Herpes Simplex Virus in astrocyte cultures. In addition, iNOS expression was detectable by RT-PCR in all batches of astrocytes tested when stimulated with a cytokine cocktail of IFN-gamma, TNF-alpha, IL-1 and LPS. Furthermore, we found that the amount of nitric oxide produced by astrocytes is not sufficient to inhibit either toxoplasmal or bacterial growth. Co-activation of iNOS and IDO on the other hand, results in an inhibition of IDO activity in astrocytes.
Insights
Human astrocytes activated by interferon-gamma inhibit Toxoplasma gondii growth via indoleamine 2,3-dioxygenase (IDO). This IDO activity also impacts other pathogens, revealing a key astrocyte defense mechanism against infections like toxoplasmic encephalitis.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Toxoplasmic encephalitis is a severe complication of toxoplasmosis.
- Astrocytes play a role in brain defense but their exact function against Toxoplasma gondii is unclear.
- Key defense mechanisms include inducible nitric oxide synthase (iNOS) and indoleamine 2,3-dioxygenase (IDO).
Purpose of the Study:
- To investigate the role of human astrocytes in defense against Toxoplasma gondii.
- To determine if astrocytes express IDO activity and if it inhibits pathogen growth.
- To assess the combined effects of iNOS and IDO in astrocyte defense.
Main Methods:
- Human astrocytes were activated with interferon-gamma (IFN-γ).
- IDO mRNA and protein expression were confirmed using RT-PCR and Western blots.
- Enzyme activity was measured, and pathogen growth inhibition was assessed.
- iNOS expression was also evaluated.
Main Results:
- IFN-γ-activated human astrocytes exhibit significant IDO activity.
- This IDO activity effectively inhibits the growth of Toxoplasma gondii and group B streptococci.
- IFN-γ-induced IDO also inhibits Herpes Simplex Virus growth in astrocytes.
- While iNOS is expressed, the nitric oxide produced is insufficient to inhibit pathogen growth.
- Co-activation of iNOS and IDO leads to inhibition of IDO activity.
Conclusions:
- Human astrocytes possess an IFN-γ-inducible IDO-mediated defense mechanism against Toxoplasma gondii.
- IDO activity in astrocytes is a crucial factor in controlling parasitic, bacterial, and viral infections.
- The interplay between iNOS and IDO warrants further investigation for understanding astrocyte-mediated immunity.
