Sunday, 28 January 2018

Astrocyte as bad guys. A piece in the jigsaw

Whilst hunting through some papers MD2 came across the following paper. I don't remember seeing it and don't remember posting on it, so a year late, I thought I would give it an airing especially since the senior author recently passed away.
However we are looking for Jigsaw pieces to help understand progressive MS and this, which looks at astrocyte activity, may be one of them


Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, M√ľnch AE, Chung WS, Peterson TC, Wilton DK, Frouin A, Napier BA, Panicker N, Kumar M, Buckwalter MS, Rowitch DH, Dawson VL, Dawson TM, Stevens B, Barres BA.Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541(7638):481-487. doi: 10.1038/nature21029.

Astrocytes are probably the most overlooked glial cell in MS
They are important and support many functions:
  • Structural: They are involved in the physical structuring of the brain. Astrocytes get their name because they are "star-shaped". They are the most abundant glial cells in the brain that are closely associated with neuronal synapses. They regulate the transmission of electrical impulses within the brain.
  • Glycogen fuel reserve buffer: Astrocytes contain glycogen and are capable of glycogenesis. Thus, astrocytes can fuel neurons with glucose during periods of high rate of glucose consumption and glucose shortage. 
  • Metabolic support: They provide neurons with nutrients such as lactate.
  • Blood–brain barrier: The astrocyte end-feet encircling endothelial cells were thought to aid in the maintenance of the blood–brain barrier.
  • Transmitter uptake and release: Astrocytes express plasma membrane transporters such as glutamate transporters for several neurotransmitters, including glutamate, ATP, and GABA
  • Regulation of ion concentration in the extracellular space: Astrocytes express potassium channels at a high density. When neurons are active, they release potassium, increasing the local extracellular concentration. Because astrocytes are highly permeable to potassium, they rapidly clear the excess accumulation in the extracellular space.[
  • Modulation of synaptic transmission and memory formation
  • Vasomodulation: Astrocytes may serve as intermediaries in neuronal regulation of blood flow.
  • Promotion of the myelinating activity of oligodendrocytes: Electrical activity in neurons causes them to release ATP, which serves as an important stimulus for myelin to form. However, the ATP does not act directly on oligodendrocytes. Instead, it causes astrocytes to secrete cytokine leukemia inhibitory factor (LIF), a regulatory protein that promotes the myelinating activity of oligodendrocytes. 
  • Nervous system repair: Upon injury to nerve cells within the central nervous system, astrocytes fill up the space to form a glial scar, and may contribute to neural repair. Although, the glial scar has traditionally been described as an impermeable barrier to regeneration.

Neuroinflammation and ischeamia induced two different types of reactive astrocytes, termed “A1” and “A2,” respectively. This terminology parallels the “M1” and “M2” macrophage nomenclature, which has also been applied to microglia in the CNS. 


In this study they talk about astrocytes, as being bad (A1) and good (A2) guys. 

A1 (Toxic) astrocytes, which are induced by injury, neuroinflammation, and neurodegenerative disease, produce proinflammatory molecules. 


A2 (Trophic) astrocytes secrete molecules that provide neurotrophic support and modulate inflammatory responses. This astrocyte phenotype is present following ischemia and has been shown to promote neuronal survival and tissue repair.

They showed that three proteins called interleukin-1 alpha. This is an immunoregulatory molecule that can help production of tumour necrosis factor alpha, which is another one of the proteins that has immunoregulatory function and  complement component 1, Subcomponent q, which is part of the antibody killing pathway and a molecule involved in cell aging drive the production of A1 astrocytes.

So can block them?

There Interleukin_1_receptor_antagonistwhich mops up IL-1 but you would need loads of it to get into the brain and being a protein this isn't going to happen very much. Same problem is for the neutralizing antibodies available and as IL-1 has some many function, block this pathway every where long term-isn't going to be good news. As for C1q, well we have the humble aspirin.

There are lots of anti-TNFs that are available, but they can stimulate memory B cells and they can and sometimes do make MS worse. 

However this study indicates that you want the anti-TNF need to get into the brain, so antibodies are not the sensible way to go this. However there are anti-TNF chemicals such as thalidomide and less tetragenic (creates deformities in unborn babies) variants. Their are phosphodiesterase 4 inhibitors (PDE4) like rolipram which has made MS worse and ibudilast which has completed a trial in SPMS recently. We showed many years ago that you needed to inhibit the TNF in the brain



These molecules all come from hot microglia, which in this study was mimicked by an infection

Once the A1s had become the bad guys you didn't need to keep giving them the three cytokines to keep them bad. Once formed they were mean bad-ass cells for good. 

However they could be salvaged and it was found that it was partially possible to make the cells more astrocyte like again.

This was done by treating A1 astrocytes with the anti-inflammatory molecules transforming growth factor beta , a cytokine with immunoregulatory activity and Fibroblast growth factor cytokine that makes fibroblasts grow in part turns them back into a normal astrocyte.

So great let's stick TGFbeta into MS and that's sorted? 

However, some neuross did this in MS with active cytokine and not the natural cytokine and disaster struct. 

The trial was stopped because TGFbeta did not just do what they wanted but it bound to TGFbeta receptor where ever it was and activated the cells it bound to. 

This just happened to be fibroblasts (which are involved in tissue modeling), they grew like mad and cause fibrosis of the kidney. 

In nature, TGF-beta is not produced as an active molecule. The active site is covered by a latent protein cap/shell that has to be cleaved to make an active molecule. This means it can travel round the body and is not active thing unless there is the right environment, such as inflammation, to cleave the latent protein.
Likewise if we start injecting Fibroblast growth factor,I now think you can what would happen.....yep probably more fibrosis in the kidneys and liver and the lungs which are going to filter the proteins.

A1 astrocytes lose many typical astrocytic functions. They showed that A1 astrocytes no longer promote neuronal survival, outgrowth, and synapse formation, or phagocytize synapses or debris. 


Importantly they suggest that A1 astrocytes secrete a compound that is toxic to neural cells.  What is it/are they?

Well a recent paper suggests something


Li S, Uno Y, Rudolph U, Cobb J, Liu J, Anderson T, Levy D, Balu DT, Coyle JT. Astrocytes in primary cultures express serine racemase, synthesize d-serine and acquire A1reactive astrocyte features. Biochem Pharmacol. 2018. pii: S0006-2952(17)30735-9.

d-Serine is a co-agonist at forebrain N-methyl-d-aspartate receptors (NMDAR) and is synthesized by serine racemase (SR). A1 reactive astrocytes express SR and release d-serine under pathologic conditions, which may contribute to their neurotoxic effects by activating extra-synaptic NMDA receptors.

So we have the hot micorglia. One way to get these as shown here was via toll-like receptor 4 and infection signals. But we can bring in other ideas in how B cells and B cell products could be key drivers in creating the hot microglia.

So the axis of evil could be

B cells------Hot Microglial-------Astrocytes-----Nerve damage

Plus abit more
B cells------Nerve damage
B cells------Hot Micrroglia-------Nerve damage
T cells------Hot Microglia--------Nerve damage
Infection---Hot Microglia--------Nerve damage

There are many targets in these pathways the central issue is to find those that do not cause too many side-effect

9 comments:

  1. Great post MD-thanks. It seems like there is one commonality/answer in all the pathways-hot microglia, not the B-cells which are recruited by hot microglia. If there is a way to inhibit or shift microglia from hot/activated status do you think that would stop the B-cell, T-cell and A1 responses MD and hence relapses or progression of MS?

    ReplyDelete
    Replies
    1. Is there a way to shift hot microglia...yes I think so.

      I think there is the relapsing component and the progressive component.

      The problem with microglia is what pathway can be targeteed that is not occurring in all the other macrophages around the body, because this will lead to side effects.

      Delete
    2. I just bumped into this: Hydroxychloroquine, an antimalarial drug that is mostly used in RA and SLE, is in trial for PPMS

      HCQ treatment reduces the activation of human microglia in vitro, delays the onset of EAE, and decreases the representation of activated macrophages/microglia and demyelination in the spinal cord of treated mice.

      https://www.ncbi.nlm.nih.gov/pubmed/26344560

      Delete
  2. https://www.youtube.com/watch?v=rfepM3L7Pqc

    Obrigado

    ReplyDelete
  3. Any chance that the glie (astrocytes and/or oligodendrocyted) might be infected by EBV?

    ReplyDelete
    Replies
    1. Yes

      " Furthermore, using double-staining we show for the first time that astrocytes and microglia, in addition to B-cells can also be infected. "

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796799/

      Delete
  4. Benfotiamine (a synthetic S-acyl derivative of thiamine (vitamin B1) Attenuates Inflammatory Response in LPS Stimulated BV-2 Microglia

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4335016/

    "Therefore, benfotiamine may have therapeutic potential for neurodegenerative diseases by inhibiting inflammatory mediators and enhancing anti-inflammatory factor production in activated microglia."


    Benfotiamine might hold promise for MS.

    ReplyDelete
    Replies
    1. Thanks we are looking for agents it can go in the mix

      Delete

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