NFκB signaling drives pro-granulocytic astroglial responses to neuromyelitis optica patient IgG

Journal of Neuroinflammation

Charles L. Howe³  Claudia F. Lucchinetti¹  Patrick D. Fitz-Gibbon²  Christina B. McCarthy¹  Renee K. Johnson¹  Yong Guo¹  Margaret E. Walker-Caulfield¹ 

[1] Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester 55905, MN, USA;Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA;Department of Immunology, Mayo Clinic, Rochester, MN, USA

关键词: NFκB;    Reactive astrocyte;    NMO;    Bortezomib;    PR-957;   

Others  :  1228650
DOI  :  10.1186/s12974-015-0403-8

 received in 2015-08-13, accepted in 2015-09-22,  发布年份 2015

【 摘 要 】

Background

Astrocytes expressing the aquaporin-4 water channel are a primary target of pathogenic, disease-specific immunoglobulins (IgG) found in patients with neuromyelitis optica (NMO). Immunopathological analyses of active NMO lesions highlight a unique inflammatory phenotype marked by infiltration of granulocytes. Previous studies characterized this granulocytic infiltrate as a response to vasculocentric complement activation and localized tissue destruction. In contrast, we observe that granulocytic infiltration in NMO lesions occurs independently of complement-mediated tissue destruction or active demyelination. These immunopathological findings led to the hypothesis that NMO IgG stimulates astrocyte signaling that is responsible for granulocytic recruitment in NMO.

Methods

Histopathology was performed on archival formalin-fixed paraffin-embedded autopsy-derived CNS tissue from 23 patients clinically and pathologically diagnosed with NMO or NMO spectrum disorder. Primary murine astroglial cultures were stimulated with IgG isolated from NMO patients or control IgG from healthy donors. Transcriptional responses were assessed by microarray, and translational responses were measured by ELISA. Signaling through the NFκB pathway was measured by western blotting and immunostaining.

Results

Stimulation of primary murine astroglial cultures with NMO IgG elicited a reactive and inflammatory transcriptional response that involved signaling through the canonical NFκB pathway. This signaling resulted in the release of pro-granulocytic chemokines and was inhibited by the clinically relevant proteasome inhibitors bortezomib and PR-957.

Conclusions

We propose that the astrocytic NFκB-dependent inflammatory response to stimulation by NMO IgG represents one of the earliest events in NMO pathogenesis, providing a target for therapeutic intervention upstream of irreversible cell death and tissue damage.

【 授权许可】

   
2015 Walker-Caulfield et al.

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