Reactive astrocytes are strongly induced by central nervous system (CNS) injury and disease, but their role is poorly understood. Here we show that a subtype of reactive astrocytes, which we termed A1, is induced by classically activated neuroinflammatory microglia. We show that activated microglia induce A1 astrocytes by secreting Il-1α, TNF and C1q, and that these cytokines together are necessary and sufficient to induce A1 astrocytes. A1 astrocytes lose the ability to promote neuronal survival, outgrowth, synaptogenesis and phagocytosis, and induce the death of neurons and oligodendrocytes. Death of axotomized CNS neurons in vivo is prevented when the formation of A1 astrocytes is blocked. Finally, we show that A1 astrocytes are abundant in various human neurodegenerative diseases including Alzheimer’s, Huntington’s and Parkinson’s disease, amyotrophic lateral sclerosis and multiple sclerosis. Taken together these findings help to explain why CNS neurons die after axotomy, strongly suggest that A1 astrocytes contribute to the death of neurons and oligodendrocytes in neurodegenerative disorders, and provide opportunities for the development of new treatments for these diseases.
- Inflammation activates microglia
- Activated microglia produced a gliotic astrocyte to be produced
- These gliotic A1 astrocytes block oligodendrocyte formation
- These gliotic A1 astrocytes are neurotoxic and make toxic elements to kill nerves
- Blocking A1 astrocytes may slow nerve loss
- Progressive MS is likely to involve glial inflammation
They are also the major scar forming cell in the demyelinated lesion and so contribute to lack of remyelination. When astrocytes are activated some people call them “reactive astrocytes” other people including me would call them “gliotic” where they put out more proteins including glial fibrillary acidi proteiin ( a hall mark of astrocytes) and many years ago I showed that they contain lots of IL-6 at least in the mouse. In this study term an reactive astrocyte subset and call it A1. However this should not be confused if you read about type I and type II astrocyttes.
This study shows that activated microglial produce some inflammatory mediators and this helps create the astrocytes. These are a complement component and interleukin-1 and tumor necrosis factor, which are well known pro-inflammatory mediators produced by inflammatory such as microglia and other cells….the other cells may relate to why blocking TNF can lead to demyelinating disease and MS worsening.
A1 astrocytes, which are present in diseases associated with neurodegeneration, lose the ability to promote neuronal survival, nerve outgrowth, synaptogenesis and phagocytosis, and induce the death of neurons and oligodendrocytes.
A1 astrocytes loose the ability to promote nerve survival and induce the death of nerves and oligodendrocytes. So this allows you to have nerve damage without needing a T or a B cell anywhere near the system. Importantly if you cut/transect the axon to simulate damage then the death of axotomized CNS neurons is prevented when the formation of A1 astrocytes is blocked,
Therefore, targeting this process may slow the processes of neurodegeneration, but is the the T and B cell theory intact.
We have been saying for some time that you have to control the glial inflammation to control progression. There is a toxic factor. What is it? This is a new part of a jigsaw, but this does not change my world view.
This aspect that was targeted in the Progressive Alliance by a group in Harvard. We know that astrocytes control the glutamate-glutamine cycle and we know how important this may be in glutamate excitotixicity killing nerves. In this case they produce toxic factors that did not support nerve survival and also they block the proliferation of oligodedrocytes and so would inhibit remyelination. It has been known for some time that astrocytes block remyelination
Neuroprotection in a novel mouse model of multiple sclerosis.
Lidster K, Jackson SJ, Ahmed Z, Munro P, Coffey P, Giovannoni G, Baker MD, Baker D. PLoS One. 2013;8(11):e79188.
Likewise there is perhaps issues with the statement that there are FDA approved inhibitors of the molecules. Whilst these A1 cells are formed by TNF, blocking this in MS is a no-no. It makes MS worse or causes demyelinating disease.
Interleukin-1, blockade of this may be interesting but as it is a globally used cytokine involved in the generation of all sorts of cells, it will not come without side effects.
Is this enough to treat progression?
Comabella M, Julià E, Tintoré M, Brieva L, Téllez N, Río J, López C, Rovira A, Montalban X. Induction of serum soluble tumor necrosis factor receptor II (sTNF-RII) and interleukin-1 receptor antagonist (IL-1ra) by interferon beta-1b in patients with progressive multiple sclerosis. J Neurol. 2008; 255:1136-41.
Soluble receptor blocks TNF and IL-1Ra blocks IL-1, but is beta interferon great for progression…not really.
However, the plus side it gives a focus on astrocytes..on the bad side we will now see a sea of uninterpretable acute EAE experiments with astrocyte conditional knockout mice that are not particularly directly relevant to astrocyte activity in progressive MS:-)