Effect of NMO-IgG on the interleukin-6 cascade in astrocytes via activation of the JAK/STAT3 signaling pathway.

Abstract

AIMS:

Astrocytes expressing the aquaporin-4 (AQP4) water channel are pathogenic, disease specific immunoglobulins (IgG) found in neuromyelitis optica spectrum disorder (NMOSD), referred to as NMO-IgG, which targets astrocytic AQP4. The interleukin-6 (IL-6) signaling when astrocytes were exposed to NMO-IgG present in the serum of NMOSD patients was evaluated.

MAIN METHODS:

Serum or human-IgG from NMOSD or healthy controls were exposed to astrocytes. The selectivity and immuno-pathological consequences of Ig binding to surface epitopes were measured by confocal microscopy. Astrocytes were exposed to medium, IL-6, soluble IL-6 receptor (sIL-6R), IL-6 + sIL-6R (IL-6/R), NMO-IgG or control-IgG, NMO-IgG + IL-6/R. The expression of key proteins in IL-6 signaling pathway, IL-6 cytokine and mRNA levels were evaluated by western blotting, enzyme-linked immunosorbent assay and quantitative polymerase chain reaction, respectively.

KEY FINDINGS:

Serum or NMO-IgG from NMOSD patients both induced the rapid downregulation of AQP4 expression on the surface of astrocytes. Stimulation of astrocytes with NMO-IgG, IL-6/R, and NMO-IgG + IL-6/R resulted in the enhancement of IL-6 mRNA expression. Meanwhile, the exogenous addition of NMO-IgG elicited an inflammatory transcriptional response that involved signaling through the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway. Inhibition of the IL-6/JAK/STAT3 pathway with the JAK1/2 specific inhibitor, AZD1480, reversed the associated increase of IL-6.

SIGNIFICANCE:

Our findings suggest that NMO-IgG can stimulate the astrocytic JAK1/2/STAT3-dependent inflammatory response, which represents one of the important events in NMO pathogenesis. Inhibition of the JAK1/2 signaling pathway may be a novel promising therapy for NMOSD.

• Authors: Li Du, Haoxiao Chang, Wangshu Xu, Yuzhen Wei, Yupeng Wang, Linlin Yin, Xinghu Zhang
• Journal: Life sciences (Life Sci) Vol. 258 Pg. 118217 (Oct 01 2020) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 32768575 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Autoantibodies
• IL6 protein, human
• Immunoglobulin G
• Interleukin-6
• STAT3 Transcription Factor
• STAT3 protein, human
• Janus Kinases

Topics

• Adult
• Aged
• Animals
• Astrocytes (drug effects, metabolism)
• Autoantibodies (blood, pharmacology)
• Cells, Cultured
• Female
• Humans
• Immunoglobulin G (blood, pharmacology)
• Interleukin-6 (agonists, metabolism)
• Janus Kinases (metabolism)
• Male
• Middle Aged
• Neuromyelitis Optica (blood)
• Rats
• Rats, Wistar
• STAT3 Transcription Factor (agonists, metabolism)
• Signal Transduction (drug effects, physiology)
• Young Adult