Wednesday, 23 May 2018

Microglial Control of Astrocytes

There is cross talk between glial cells in the CNS, which will contribute to inflammation and damage.

Today we have a science post from animals (If not interested don't read on) looking at mechanisms of this
Microglial control of astrocytes in response to microbial metabolites.
Rothhammer V, Borucki DM, Tjon EC, Takenaka MC, Chao CC, Ardura-Fabregat A, de Lima KA, Gutiérrez-Vázquez C, Hewson P, Staszewski O, Blain M, Healy L, Neziraj T, Borio M, Wheeler M, Dragin LL, Laplaud DA, Antel J, Alvarez JI, Prinz M, Quintana FJ.
Nature. 2018 May 16. doi: 10.1038/s41586-018-0119-x. [Epub ahead of print]

Microglia and astrocytes modulate inflammation and neurodegeneration in the central nervous system (CNS). Microglia modulate pro-inflammatory and neurotoxic activities in astrocytes. Here we report that TGFα and VEGF-B produced by microglia regulate the pathogenic activities of astrocytes in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Microglia-derived TGFα acts via the ErbB1 receptor in astrocytes to limit their pathogenic activities and EAE development. Conversely, microglial VEGF-B triggers FLT-1 signalling in astrocytes and worsens EAE. VEGF-B and TGFα also participate in the microglial control of human astrocytes. Furthermore, expression of TGFα and VEGF-B in CD14+ cells correlates with the multiple sclerosis lesion stage. Finally, metabolites of dietary tryptophan produced by the commensal flora control microglial activation and TGFα and VEGF-B production, modulating the transcriptional program of astrocytes and CNS inflammation through a mechanism mediated by the aryl hydrocarbon receptor. In summary, we identified positive and negative regulators that mediate the microglial control of astrocytes. Moreover, these findings define a pathway through which microbial metabolites limit pathogenic activities of microglia and astrocytes, and suppress CNS inflammation. This pathway may guide new therapies for multiple sclerosis and other neurological disorders.
                                                
In this study it is reported that depletion of aryl hydrocarbon receptor (AHR) worsened EAE. 

If you look at BrainSeq website you can see that activated microglai really express this receptor  

                                           AHR expression in mice brain
                  
                                              AHR expression in human brain
Microglia expression of AHR increases on microglia after activation

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.


You can see loss of AHR from microglia (CXCR1 positive) inhibits EAE. This can be seen bottom right above. Now we can take this on face value that this is the case. There is no reason not to believe this. However, we can also look at the output of EAE from the same lab and you can see something.

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.

2 comments:

  1. I just came on to see if you'd seen this. Here's more coverage (with more plain English ahem [though grateful for all you do on the blog!]):

    https://www.forbes.com/sites/victoriaforster/2018/05/16/researchers-uncover-gut-bacterias-potential-role-in-multiple-sclerosis/#44b8de0d4232

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