Life science
Medical & healthcare, Drug development

Novel therapeutic strategy for NMO: RGMa-mAb foundeffective against CNS inflammation
Neuro-Medical Science, Molecular Neuroscience, Graduate School of Medicine
Specially Appointed Associate Professor Takahide Itokazu

https://researchmap.jp/22360679

Molecular Neuroscience, Neuro-Medical Science, Graduate School of Medicine
Professor Toshihide Yamashita

Life science

Abstract
Neuromyelitis optica (NMO) is a currently incurable immune-mediated inflammatory disorder of the central nervous system (CNS).
In the present study, using a clinically relevant NMO rat modeland an NMO-autopsied human samples, we provide new insights
on the pathophysiological mechanism of NMO, and show thatan antibody against repulsive guidance molecule-a (RGMa) canameliorate NMO-associated motor deficit and neuropathic pain byinterrupting the interplay between immune cells, specifically macrophages and neutrophils.

https://researchmap.jp/ToshihideYamashita

may provide an efficient therapeutic strategy for treating wide
range of CNS diseases.

▍ Background & Results

A key feature of NMO is “perivascular astrocytopathy”, that iscaused by the leakage of pathogenic autoantibodies against thewater channel protein aquaporin-4 (AQP4) into the CNS. Acute
NMO attacks are frequently severe, causing visual loss, paraplegia, intractable neuropathic pain, and death.
RGMa is a membrane-associated glycosylphosphatidylinositol-anchored glycoprotein which has multiple functions including
neurite growth inhibition and immune regulation, and has been implicated in various central nervous system (CNS) disorders such as
multiple sclerosis and spinal cord injury.
In the present study, we investigated the possible involvement of
RGMa signaling in the pathology of CNS inflammation under NMOcondition. We found that, both in NMO rats and NMO-autopsied
human samples, RGMa is expressed by neurons and astrocytes,
whereas its receptor neogenin is expressed by infiltrating macrophages. Exploiting their contribution, we treated the NMO rats
with anti-RGMa neutralizing antibody and evaluated the therapeutic effect by behavioral testing (motor symptom and neuropathicpain), immunohistochemistry, and gene expression study. Anti-RGMa antibody treatment resulted in less astrocytic death and decreased clinical symptoms. Interestingly, we found that RGMa-mAb
treatment clearly suppressed neutrophil infiltration along with decreased expression of neutrophil-attracting chemokines. We thenfound that neogenin-expressing macrophages accumulated in thelesion site expressed strong neutrophil chemoattractants. Further
analysis revealed that RGMa directly regulated the expression ofchemoattractants in macrophages. Therefore, RGMa signaling ininfiltrated macrophages is considered as a critical driver of neutrophil-related astrocytopathy in NMO lesions.

▍ Significance of the research and Future perspective
Our findings revealed a new molecular mechanism of NMO
pathophysiology in which RGMa stimulates macrophages to attract
neutrophils to the lesions, that lead to the exacerbation of CNS inflammation. The interplay between macrophages and neutrophils
revealed by our present study is possibly shared by a variety ofCNS inflammatory conditions. Therefore, RGMa-mAb treatment

P a t e n t Japanese Patent Application No. 2021-567731
Iwamoto, Shosuke; Itokazu, Takahide; Yamashita, Toshihide et al. RGMa signal in Macrophages Induces Neutrophil-related Astrocytopathy in NMO. Annals
Tr e a t i s eof Neurology. 2022, 91, p. 532-547, doi: 10.1002/ana.26327
URL https://www.med.osaka-u.ac.jp/pub/molneu/index_e.html
K e y w o r d neuromyelitis optica, macrophage, RGMa