AHR expression in human brain
Microglial can activate astrocytes and vice versa and so this could contribute to damage during MS.
Bioinformatic analyses aimed to identify candidate cause and effect relationships between dysregulated transcriptional responses in microglia and astrocytes identified two transcriptional modules in astrocytes, potentially controlled by microglia-produced transforming growth factor alpha (Tgfa) and and vascular endothelial growth factor beta (Vegfb) during EAE. Microglial AHR deletion decreased Tgfa and increased Vegfb expression during EAE.
VEGF-B pretreatment enhanced the toxicity of astrocytes towards neurons and oligodendrocytes; TGFα reduced this toxicity.
Microglial Tgfa knockdown worsened EAE, whereas Vegfb knockdown ameliorated it. They then targeted the downstream signaling molecules of Tgfa(Erbb1) and Vegfb (Fit1) and got the same result, so science two ways.
The microbial metabolism of dietary tryptophan (Trp) generates AHR agonists such as I3S, which limits astrocyte pathogenic activities and EAE development. Trp or I3S administration ameliorated EAE in control but not in microglail AHR-deficient mice, suggesting that microglial AHR participates in EAE amelioration by Trp metabolites.
Finally, they analysed AHR, TGFα and VEGF-B expression on brain samples from patients with MS. We detected AHR, TGFα and VEGF-B expression in CD14+ cells (microglia and recruited monocytes) in the normally appearing white matter (NAWM), demyelinated active and chronic multiple sclerosis (MS) lesions; the highest AHR, VEGF-B and TGFα expression was detected in CD14+ cells in MS active lesions
In summary, they found that AHR-controlled microglial VEGF-B and TGFα regulate astrocyte pathogenic activities during EAE and define a gut–brain axis by which metabolites of dietary Trp controlled by the commensal flora act directly on CNS-resident microglia and astrocytes to limit inflammation via AHR.
So a nice piece of science, published in the Journal Nature
This is all well and dandy as the data all fits. However are the conclusions robust?
Will it pan out? We have to wait until someone repeats this.
It is not the treatment that shows the effect it is what happens to the control group that dictates the message.
When the treatment worsens things the control group ain’t that great. When it makes things better the control group is as good as the worsening in the other experiments. Therefore, there is a quality control in the experiments and the control group is not staying the same. No quality control and reader beware.