Human macrophages convert <scp>l</scp>-tryptophan into the neurotoxin quinolinic acid

TLDR

Immune activation leads to accumulation of the neurotoxin quinolinic acid in the human CNS, yet it is unclear whether microglia synthesize it. The authors incubated human microglia, peripheral blood macrophages, and fetal brain cells with [13C6]L‑tryptophan ± interferon‑γ and quantified resulting [13C6]quinolinic acid by GC‑ECNI‑MS. Unstimulated microglia and macrophages produce L‑kynurenine and quinolinic acid, interferon‑γ further increases L‑kynurenine, and microglia and macrophages generate up to 1.4 µM quinolinic acid while fetal brain cells produce <2 nM, indicating activated microglia/macrophages are a major CNS source of this neurotoxin.

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.