Human microglia convert l-tryptophan into the neurotoxin quinolinic acid
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Published on: October 25, 2016
M P Heyes1, C L Achim, C A Wiley
1Section on Analytical Biochemistry, National Institute of Mental Health, Bethesda, MD 20892, USA.
Abstract:
Immune activation leads to accumulations of the neurotoxin and kynurenine pathway metabolite quinolinic acid within the central nervous system of human patients. Whereas macrophages can convert L-tryptophan to quinolinic acid, it is not known whether human brain microglia can synthesize quinolinic acid. Human microglia, peripheral blood macrophages and cultures of human fetal brain cells (astrocytes and neurons) were incubated with [13C6]L-tryptophan in the absence or presence of interferon gamma. [13C6]Quinolinic acid was identified and quantified by gas chromatography and electron-capture negative-chemical ionization mass spectrometry. Both L-kynurenine and [13C6]quinolinic acid were produced by unstimulated cultures of microglia and macrophages. Interferon gamma, an inducer of indoleamine 2,3-dioxygenase, increased the accumulation of L-kynurenine by all three cell types (to more than 40 microM). Whereas large quantities of [13C6]quinolinic acid were produced by microglia and macrophages (to 438 and 1410 nM respectively), minute quantities of [13C6]quinolinic acid were produced in human fetal brain cultures (not more than 2 nM). Activated microglia and macrophage infiltrates into the brain might be an important source of accelerated conversion of L-tryptophan into quinolinic acid within the central nervous system in inflammatory diseases.
Insights
Human microglia and macrophages can produce quinolinic acid, a neurotoxin linked to immune activation. This finding suggests these immune cells may contribute to quinolinic acid accumulation in the brain during inflammatory diseases.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Immune activation elevates quinolinic acid, a neurotoxin and kynurenine pathway metabolite, in the human central nervous system.
- Macrophages convert L-tryptophan to quinolinic acid, but microglia's capacity for this synthesis is unknown.
Purpose of the Study:
- To investigate whether human brain microglia can synthesize quinolinic acid.
- To compare quinolinic acid production by microglia, macrophages, and human fetal brain cell cultures.
Main Methods:
- Incubation of human microglia, peripheral blood macrophages, and human fetal brain cells (astrocytes, neurons) with [13C6]L-tryptophan.
- Use of gas chromatography and electron-capture negative-chemical ionization mass spectrometry for identification and quantification of [13C6]quinolinic acid.
- Treatment with interferon gamma to assess its effect on indoleamine 2,3-dioxygenase activity and metabolite accumulation.
Main Results:
- Unstimulated microglia and macrophages produced both L-kynurenine and [13C6]quinolinic acid.
- Interferon gamma significantly increased L-kynurenine accumulation in all cell types.
- Microglia and macrophages produced substantial amounts of [13C6]quinolinic acid, while human fetal brain cultures produced only minute quantities.
Conclusions:
- Human microglia, like macrophages, can synthesize quinolinic acid from L-tryptophan.
- Activated microglia and macrophages in the brain may be significant sources of quinolinic acid during inflammatory diseases.
- This highlights a potential mechanism for neurotoxin accumulation in central nervous system inflammatory conditions.
