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Astrocyte-microglia interaction drives evolving neuromyelitis optica lesion
- Source :
- Journal of Clinical Investigation. August, 2020, Vol. 130 Issue 8, p4025, 14 p.
- Publication Year :
- 2020
-
Abstract
- Neuromyelitis optica (NMO) is a severe inflammatory autoimmune CNS disorder triggered by binding of an IgG autoantibody to the aquaporin 4 (AQP4) water channel on astrocytes. Activation of cytolytic complement has been implicated as the major effector of tissue destruction that secondarily involves myelin. We investigated early precytolytic events in the evolving pathophysiology of NMO in mice by continuously infusing IgG (NMO patient serum-derived or AQP4-specific mouse monoclonal), without exogenous complement, into the spinal subarachnoid space. Motor impairment and sublytic NMO-compatible immunopathology were IgG dose dependent, AQP4 dependent, and, unexpectedly, microglia dependent. In vivo spinal cord imaging revealed a striking physical interaction between microglia and astrocytes that required signaling from astrocytes by the C3a fragment of their upregulated complement C3 protein. Astrocytes remained viable but lost AQP4. Previously unappreciated crosstalk between astrocytes and microglia involving early-activated CNS-intrinsic complement components and microglial C3a receptor signaling appears to be a critical driver of the precytolytic phase in the evolving NMO lesion, including initial motor impairment. Our results indicate that microglia merit consideration as a potential target for NMO therapeutic intervention.<br />Introduction Neuromyelitis optica (NMO) is an inflammatory autoimmune disorder of the central nervous system (CNS) with secondary myelin loss. It disproportionately affects women and non-White populations, typically presents as optic [...]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 130
- Issue :
- 8
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.633717377
- Full Text :
- https://doi.org/10.1172/JCI134816