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Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in

Dimitrios Davalos1, Jae Kyu Ryu, Mario Merlini

  • 1Gladstone Institute of Neurological Disease, University of California, San Francisco, 1650 Owens Street, San Francisco, CA 94158, USA.

Nature Communications
|November 29, 2012
PubMed

Insights

Fibrinogen, a blood protein, triggers early microglial immune responses near blood vessels, contributing to axonal damage in neuroinflammation. Blocking fibrinogen prevents this damage, revealing a key mechanism in multiple sclerosis.

Area of Science:

  • Neuroimmunology
  • Neuroinflammation
  • Multiple Sclerosis Pathogenesis

Background:

  • Multiple sclerosis involves blood-brain barrier disruption, microglial activation, and neurodegeneration.
  • The initial triggers for innate immune responses and their role in axonal damage are not fully understood.

Purpose of the Study:

  • To investigate the role of blood proteins in initiating microglial responses and axonal damage in neuroinflammation.
  • To identify specific triggers for early innate immune activation in the context of blood-brain barrier disruption.

Main Methods:

  • In vivo two-photon microscopy to observe microglial behavior in real-time.
  • Assessing the effects of fibrinogen on microglial clustering and reactive oxygen species release.
  • Utilizing anticoagulant treatment and genetic modification to block fibrinogen interactions.

Main Results:

  • Microglia form perivascular clusters prior to myelin loss or paralysis onset.
  • Fibrinogen specifically induces rapid and sustained microglial responses in vivo.
  • Fibrinogen leakage correlates with axonal damage and triggers reactive oxygen species release from microglia.
  • Inhibition of fibrin formation or fibrinogen-CD11b/CD18 interaction prevents microglial clustering and axonal damage.

Conclusions:

  • Early perivascular microglial clustering, triggered by fibrinogen leakage, contributes significantly to axonal damage in neuroinflammatory diseases.
  • Fibrinogen acts as a crucial initiator of innate immune responses at the vasculature in neuroinflammation.
  • Targeting fibrinogen or its receptor interactions may offer therapeutic strategies for neuroinflammatory conditions.

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