Thursday, 29 November 2012

Research: Blood Products triggers Microglia to cause Damage

Davalos D et al. Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation Nat. Commun. 3 : 1227 doi:10.1038/ncomms2230 (2012)
 

Blood-brain barrier disruption, microglial activation and neurodegeneration are hallmarks of multiple sclerosis. However, the initial triggers that activate innate immune responses and their role in axonal damage remain unknown. Here we show that the blood protein fibrinogen induces rapid microglial responses toward the vasculature and is required for axonal damage in neuroinflammation. Using in vivo two-photon microscopy, we demonstrate that microglia form perivascular clusters before myelin loss or paralysis onset and that, of the plasma proteins, fibrinogen specifically induces rapid and sustained microglial responses in vivo. Fibrinogen leakage correlates with areas of axonal damage and induces reactive oxygen species release in microglia. Blocking fibrin formation with anticoagulant treatment or genetically eliminating the fibrinogen binding motif recognized by the microglial integrin receptor CD11b/CD18 inhibits perivascular microglial clustering and axonal damage. Thus, early and progressive perivascular microglial clustering triggered by fibrinogen leakage upon blood-brain barrier disruption contributes to axonal damage in neuroinflammatory disease.


We have known for some time that production of elements of the blood clotting system, such as fibrin and fibrinogen are deposited in lesions of MS and EAE. It was also shown many years ago I mean many years ago, that this occurs before much infiltration occurs.

                              Green = fibrinogen around blood vessels, red = white blood cells
                                      This data is from experiments done many years ago

We recently talked about two photon microscopy and imaging in the living animal and this has been used in this current study. This suggests that leakage of blood proteins into the brain tissue can activate microglial cells to cluster as a early stage in lesion formation. This can be seen below with leakage of dextran (red) from the blood vessels into brain tissue and the clustering of microglia (green)


It was shown that if you block fibrin deposition that this can influence lesion formation, it was shown many years ago that manipulating this fibrinogen production can influence the disease. in EAE. This inhibited clusters, however if I killed of T cells it would no doubt inhibit clusters as disease would not start. The authors then suggest that fibrinogen is part of the nerve destructive process, because if they deplete fibrinogen they get less nerve damage, however as they get less lesion formation surely it is obvious that this would happen. Anyway, it is then shown that when fibrinogen activates the microglia they can produce reactive oxygen species, which can be damaging to nerves. So we seem to be agreed that macrophages/microglia can be the bad guys in generating damage. The will also be the good guys later-on clearing the damage up.

         Holes in Blood vessels as depicted above do not happen, but junctions are remodelled
           
What drives these lesions....I would say T cell derived cytokines then macrophages, microglia do the damage. In previous vidoes we have seen T cells associated with damage also.

Are these microglial clusters the same as pre-active lesions in MS, I am not sure they are as I believe pre-active lesions do not all centre on blood vessels, but stressed oligodendrocytes. With this approach any insult that releases fibrinogen would result in the same lesion, so Stroke etc, would look like MS. So there are many components that need to be layered into this view but watching events occuring in real time is revolutionising how we see events. 

Check out the Movies and also look at the reference list (e.g. 11-13 in paper) and check out the movies in previous papers, they really are spectacular.

2 comments:

  1. A great piece of work. Shows we were on the right track back in 2005!

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    Replies
    1. I agree, I think modern imaging techniques will be the way forward. I suspect you will not be the only ones who have a lifes work shown up on film.
      "Lights, Camera , Action " exciting times.
      Regards as always.

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