Astrocyte-microglia interaction drives evolving neuromyelitis optica lesion

Area of Science:

• Neuroimmunology
• Autoimmune CNS Disorders

Background:

• Neuromyelitis optica (NMO) is a severe autoimmune CNS disorder.
• It is characterized by IgG autoantibodies targeting aquaporin 4 (AQP4) on astrocytes.
• Complement activation is thought to be the primary driver of tissue destruction.

Purpose of the Study:

• To investigate early, precytolytic events in NMO pathophysiology.
• To understand the role of microglia in NMO pathogenesis without exogenous complement.

Main Methods:

• Continuous infusion of IgG (NMO patient serum or AQP4-specific monoclonal) into the spinal subarachnoid space of mice.
• In vivo spinal cord imaging to observe astrocyte-microglia interactions.
• Assessment of motor function and immunopathology.

Main Results:

• Motor impairment and NMO-compatible immunopathology were dose-dependent and AQP4-dependent.
• Microglia were unexpectedly crucial for the observed pathology.
• Astrocytes signaled to microglia via C3a fragments, leading to AQP4 loss and physical interaction, even without cytolytic complement activation.

Conclusions:

• A previously unappreciated crosstalk between astrocytes and microglia, involving CNS-intrinsic complement components and microglial C3a receptor signaling, drives the precytolytic phase of NMO.
• This astrocyte-microglia interaction is critical for initial motor impairment in NMO.
• Microglia represent a potential therapeutic target for NMO.