TY - JOUR
T1 - RGMa Signal in Macrophages Induces Neutrophil-Related Astrocytopathy in NMO
AU - Iwamoto, Shosuke
AU - Itokazu, Takahide
AU - Sasaki, Atsushi
AU - Kataoka, Hirotoshi
AU - Tanaka, Shinji
AU - Hirata, Takeshi
AU - Miwa, Keiko
AU - Suenaga, Toshihiko
AU - Takai, Yoshiki
AU - Misu, Tatsuro
AU - Fujihara, Kazuo
AU - Yamashita, Toshihide
N1 - Funding Information:
A humanized monoclonal antibody to repulsive guidance molecule‐a used in the study was developed by Osaka University, Chiba University, and Mitsubishi Tanabe Pharma Corporation and are the property of them. S.I., A.S., H.K., S.T., T.H., and K.M. are employees of Mitsubishi Tanabe Pharma Corporation. Department of Neuro‐Medical Science was co‐founded by Osaka University and Mitsubishi Tanabe Pharma Corporation. Financial support for this research was provided in part by Mitsubishi Tanabe Pharma Corporation.
Funding Information:
This work was supported by AMED‐CREST (grant number 21gm1210005h0004) and JSPS KAKENHI (grant number 21H05049 to T.Y.). The authors would like to thank Yoichiro Abe and Masato Yasui from Keio University (Tokyo, Japan), and Hiroko Iwanari and Takao Hamakubo from Tokyo University (Japan) for providing the E5415A antibody. E5415A production was supported by the project of Development of New Functional Antibody Technologies of the New Energy and Industrial Technology Development Organization (NEDO), and Hybridoma against AQP4 (E5415A) was provided by the RIKEN BRC through the National BioResource Project of the MEXT/AMED, Japan.
Funding Information:
This work was supported by AMED-CREST (grant number 21gm1210005h0004) and JSPS KAKENHI (grant number 21H05049 to T.Y.). The authors would like to thank Yoichiro Abe and Masato Yasui from Keio University (Tokyo, Japan), and Hiroko Iwanari and Takao Hamakubo from Tokyo University (Japan) for providing the E5415A antibody. E5415A production was supported by the project of Development of New Functional Antibody Technologies of the New Energy and Industrial Technology Development Organization (NEDO), and Hybridoma against AQP4 (E5415A) was provided by the RIKEN BRC through the National BioResource Project of the MEXT/AMED, Japan.
Publisher Copyright:
© 2022 American Neurological Association.
PY - 2022/4
Y1 - 2022/4
N2 - Objective: Repulsive guidance molecule-a (RGMa) is a glycosylphosphatidylinositol-linked glycoprotein which has multiple functions including axon growth inhibition and immune regulation. However, its role in the pathophysiology of neuromyelitis optica (NMO) is poorly understood. Perivascular astrocytopathy, which is induced by the leakage of aquaporin-4 (AQP4)-specific IgG into the central nervous system parenchyma, is a key feature of NMO pathology. We investigated the RGMa involvement in the pathology of NMO astrocytopathy, and tested a therapeutic potential of humanized anti-RGMa monoclonal antibody (RGMa-mAb). Methods: Using a clinically relevant NMO rat model, we evaluated the therapeutic effect of a RGMa-mAb by behavioral testing, immunohistochemistry, and gene expression assay. We further performed in vitro experiments to address the RGMa-signaling in macrophages. Results: In both NMO rats and an NMO-autopsied sample, RGMa was expressed by the spared neurons and astrocytes, whereas its receptor neogenin was expressed by infiltrating macrophages. AQP4-IgG-induced astrocytopathy and clinical exacerbation in NMO rats were ameliorated by RGMa-mAb treatment. RGMa-mAb treatment significantly suppressed neutrophil infiltration, and decreased the expression of neutrophil chemoattractants. Interestingly, neogenin-expressing macrophages accumulated in the lesion expressed CXCL2, a strong neutrophil chemoattractant, and further analysis revealed that RGMa directly regulated CXCL2 expression in macrophages. Finally, we found that our NMO rats developed neuropathic pain, and RGMa-mAb treatment effectively ameliorated the severity of neuropathic pain. Interpretation: RGMa signaling in infiltrated macrophages is a critical driver of neutrophil-related astrocytopathy in NMO lesions, and RGMa-mAb may provide an efficient therapeutic strategy for NMO-associated neuropathic pain and motor deficits in patients with NMO. ANN NEUROL 2022;91:532–547.
AB - Objective: Repulsive guidance molecule-a (RGMa) is a glycosylphosphatidylinositol-linked glycoprotein which has multiple functions including axon growth inhibition and immune regulation. However, its role in the pathophysiology of neuromyelitis optica (NMO) is poorly understood. Perivascular astrocytopathy, which is induced by the leakage of aquaporin-4 (AQP4)-specific IgG into the central nervous system parenchyma, is a key feature of NMO pathology. We investigated the RGMa involvement in the pathology of NMO astrocytopathy, and tested a therapeutic potential of humanized anti-RGMa monoclonal antibody (RGMa-mAb). Methods: Using a clinically relevant NMO rat model, we evaluated the therapeutic effect of a RGMa-mAb by behavioral testing, immunohistochemistry, and gene expression assay. We further performed in vitro experiments to address the RGMa-signaling in macrophages. Results: In both NMO rats and an NMO-autopsied sample, RGMa was expressed by the spared neurons and astrocytes, whereas its receptor neogenin was expressed by infiltrating macrophages. AQP4-IgG-induced astrocytopathy and clinical exacerbation in NMO rats were ameliorated by RGMa-mAb treatment. RGMa-mAb treatment significantly suppressed neutrophil infiltration, and decreased the expression of neutrophil chemoattractants. Interestingly, neogenin-expressing macrophages accumulated in the lesion expressed CXCL2, a strong neutrophil chemoattractant, and further analysis revealed that RGMa directly regulated CXCL2 expression in macrophages. Finally, we found that our NMO rats developed neuropathic pain, and RGMa-mAb treatment effectively ameliorated the severity of neuropathic pain. Interpretation: RGMa signaling in infiltrated macrophages is a critical driver of neutrophil-related astrocytopathy in NMO lesions, and RGMa-mAb may provide an efficient therapeutic strategy for NMO-associated neuropathic pain and motor deficits in patients with NMO. ANN NEUROL 2022;91:532–547.
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U2 - 10.1002/ana.26327
DO - 10.1002/ana.26327
M3 - Article
C2 - 35167145
AN - SCOPUS:85125836205
SN - 0364-5134
VL - 91
SP - 532
EP - 547
JO - Annals of Neurology
JF - Annals of Neurology
IS - 4
ER -