RGMa Signal in Macrophages Induces Neutrophil‐Related Astrocytopathy in NMO

Abstract

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

Impaired response of blood neutrophils to cell-death stimulus differentiates AQP4-IgG-seropositive NMOSD from MOGAD

“…Neutrophils are also found in the CNS lesions of NMO animal models [17][18][19][20][21]. Moreover, increasing evidence suggests a contribution of neutrophils to the deleterious inflammatory cascade inside the CNS [11,[17][18][19][20][21][22][23][24][25][26][27]. In line with these findings, our previous study showed that both NMOSD and MS-derived neutrophils have an activated phenotype in comparison to HC.…”

“…An increase in the circulating neutrophil-to-lymphocyte ratio (NLR) has been reported during relapse in both, APQ4 + NMOSD and MOGAD [15,16], but during remission only in APQ4 + NMOSD patients compared to healthy controls (HC) [16]. Neutrophils are also found in the CNS lesions of NMO animal models [17][18][19][20][21]. Moreover, increasing evidence suggests a contribution of neutrophils to the deleterious inflammatory cascade inside the CNS [11,[17][18][19][20][21][22][23][24][25][26][27].…”

RGMa promotes dedifferentiation of vascular smooth muscle cells into a macrophage-like phenotype in vivo and in vitro

“…There is growing acknowledgement of the involvement of RGMa in the occurrence and development of inflammatory-related diseases [14]. RGMa is also a high affinity co-receptor of bone morphogenetic proteins (BMPs) and has been demonstrated to influence iron homeostasis and endochondral bone development by activating the SMAD signaling pathway [15].…”

Humanized Anti-RGMa Antibody Treatment Promotes Repair of Blood-Spinal Cord Barrier Under Autoimmune Encephalomyelitis in Mice

“…Even in the BSCB-disrupted phase, anti-RGMa treatment drastically enhanced BBB repair in our experimental settings. For all previously reported animal models wherein anti-RGMa treatment had therapeutic effects, including spinal cord injury ( 15 , 16 ), stroke ( 17 ), and neuromyelitis optica ( 18 , 19 ), BBB/BSCB disruption is considered an important exacerbation factor. The BBB repair-enhancing effect of anti-RGMa may contribute to the amelioration of pathology in the above-mentioned models.…”

“…Repulsive guidance molecule-a (RGMa) is a membrane-associated glycosylphosphatidylinositol-anchored glycoprotein that has been implicated in various central nervous system (CNS) disorders, including MS ( 12 – 14 ), spinal cord injury ( 15 , 16 ), stroke ( 17 ), and neuromyelitis optica ( 18 – 20 ), both in experimental animal models ( 12 – 19 ) and in patients ( 12 , 13 , 16 , 19 , 20 ). In the case of MS, RGMa has been reported as upregulated in disease lesions ( 13 ), and in the experimental autoimmune encephalomyelitis (EAE) mouse model, anti-RGMa neutralizing antibody treatment was shown to attenuates motor symptoms by modulating T cell responses ( 12 ).…”