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Cytokine responses induced by Toxoplasma gondii in astrocytes and microglial cells
H G Fischer1, B Nitzgen, G Reichmann
1Institut für Medizinische Mikrobiologie und Virologie, Heinrich-Heine-Universität, Düsseldorf, Germany. hans-georg.fischer@uni-duesseldorf.de
Abstract:
To investigate the role of astroglia in intracerebral immune response to Toxoplasma gondii, astrocytes cultured from mouse brain were inoculated with mouse-virulent or -avirulent toxoplasma strains. In comparison to microglia/ brain macrophages, astrocytes as host cells allowed stronger proliferation of avirulent parasites. Toxoplasma infection of astroglia was accompanied by release of interleukin- (IL)1 alpha, IL-6, and granulocyte/macrophage colony-stimulating factor (GM-CSF) activity, whereas alternative challenge by lipopolysaccharide (LPS) evoked no IL-1 response and significantly higher titers of IL-6 and GM-CSF. At the mRNA level, both stimuli induced transcription of all three cytokines in astrocytes. Secretion of IL-1 and IL-6 upon infection was triggered by T. gondii brady- and tachyzoites in a time- and dose-dependent manner. Heat killing of parasites, but not an exposure to polymyxin B, abrogated their cytokine-inducing activity, thus indicating that an LPS-independent stimulus is provided by T. gondii. When administered in combination, LPS synergistically augmented the IL-1-inducing effect of toxoplasma infection. In comparison, T. gondii-induced, but not an LPS-triggered, IL-6 response of astrocytes resisted to antagonization with IL-10. The IL-6 response of parasitized astroglia was up-regulated by external tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta 1, with only TNF-alpha enhancing simultaneous release of IL-1. Substantial secretion of IL-10 and TNF-alpha was detected in T. gondii-infected microglia, but not in astrocyte cultures. A possibly autocrine stimulation of infected astroglia via IL-1 was found to be unlikely, since addition of IL-1 receptor antagonist did not affect the release of IL-6 and GM-CSF while inhibiting these responses in IL-1-treated cells. The findings substantiate a separate, T. gondii-induced pathway of astroglia activation characterized by the release of IL-1 which may drive local inflammatory reaction both at initial infection of the brain and during reactivating toxoplasmosis.
Insights
Toxoplasma gondii infection activates astroglia, triggering interleukin-1 (IL-1) release. This distinct pathway, independent of lipopolysaccharide (LPS), drives brain inflammation during toxoplasmosis.
Area of Science:
- Neuroimmunology
- Infectious Diseases
- Cell Biology
Background:
- Astroglia play a crucial role in the central nervous system's immune response.
- Toxoplasma gondii is an opportunistic pathogen that can cause severe neurological complications.
Purpose of the Study:
- To investigate the role of astroglia in the intracerebral immune response to Toxoplasma gondii.
- To elucidate the mechanisms of astroglia activation and cytokine production during T. gondii infection.
Main Methods:
- Primary mouse astrocyte and microglia cultures were infected with virulent and avirulent T. gondii strains.
- Cytokine release (IL-1 alpha, IL-6, GM-CSF, IL-10, TNF-alpha) was measured using various assays.
- mRNA expression of cytokines was analyzed.
- Lipopolysaccharide (LPS) and IL-1 receptor antagonist were used to modulate responses.
Main Results:
- Astrocytes supported higher proliferation of avirulent T. gondii compared to microglia.
- T. gondii infection induced IL-1 alpha, IL-6, and GM-CSF release from astrocytes, distinct from LPS-induced responses.
- T. gondii tachyzoites and bradyzoites triggered cytokine secretion in a time- and dose-dependent manner, indicating an LPS-independent stimulus.
- LPS synergistically enhanced T. gondii-induced IL-1 production.
- T. gondii-induced IL-6 response in astrocytes was resistant to IL-10 antagonism.
- Microglia, but not astrocytes, secreted significant IL-10 and TNF-alpha during infection.
Conclusions:
- T. gondii activates astroglia through a distinct pathway involving IL-1 alpha release.
- This astroglial activation contributes to local brain inflammation during initial infection and reactivation of toxoplasmosis.
- Astroglia represent a significant cellular component in the host's immune response to intracerebral T. gondii infection.