RGMA and IL21R show association with experimental inflammation and multiple sclerosis

Nohra, Rita; Beyeen, Amennai Daniel; Guo, Jian; Khademi, Mohsen; Sundqvist, Emilie; Hedreul, Mélanie Thessén; Sellebjerg, Finn; Smestad, C.; Oturai, Annette Bang; Harbo, Hanne F.; Wallström, Erik; Hillert, Jan; Alfredsson, Lars; Kockum, Ingrid; Jagodic, Maja; Lorentzen, Johnny C.; Olsson, Tomas

doi:10.1038/gene.2009.111

Cited by 61 publications

(50 citation statements)

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“…The elevation of RGMa is due to microglia/macrophages that invade the lesion site and start producing RGMa to avoid novel axonal growth (Kitayama et al, 2011); in line with this, local administration of RGMa neutralizing antibodies significantly induced axon regeneration and locomotor improvement after spinal cord injury (Hata et al, 2006). Recently, RGMa has also been associated with multiple sclerosis and autoimmune encephalomyelitis (Nohra et al, 2010;Muramatsu et al, 2011), underlining the importance of RGMa for both the adult and embryonic nervous system. The role of RGMa in delaying neurite outgrowth, growth cone repulsion, and growth cone retraction is mediated by the dependence receptor Neogenin, a homolog of DCC (Deleted in Colorectal Cancer) and known Netrin-1 receptor, and a cytoplasmatic signaling cascade that involves RhoA/Rho kinases, a family of small GTP-binding proteins that regulate cytoskeletal actin dynamics (Rajagopalan et al, 2004;Hata et al, 2006;Conrad et al, 2007;Itokazu et al, 2012).…”

Section: Introductionmentioning

confidence: 81%

RGMa and RGMb expression pattern during chicken development suggest unexpected roles for these repulsive guidance molecules in notochord formation, somitogenesis, and myogenesis

Jorge

Ahmed

Bothe

et al. 2012

Developmental Dynamics

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Background: Repulsive guidance molecules (RGM) are high-affinity ligands for the Netrin receptor Neogenin, and they are crucial for nervous system development including neural tube closure; neuronal and neural crest cell differentiation and axon guidance. Recent studies implicated RGM molecules in bone morphogenetic protein signaling, which regulates a variety of developmental processes. Moreover, a role for RGMc in iron metabolism has been established. This suggests that RGM molecules may play important roles in non-neural tissues. Results: To explore which tissues and processed may be regulated by RGM molecules, we systematically investigated the expression of RGMa and RGMb, the only RGM molecules currently known for avians, in the chicken embryo. Conclusions: Our study suggests so far unknown roles of RGM molecules in notochord, somite and skeletal muscle development. Developmental Dynamics 241: [1886][1887][1888][1889][1890][1891][1892][1893][1894][1895][1896][1897][1898][1899][1900] 2012. V C 2012 Wiley Periodicals, Inc.Key words: RGMa; DRAGON; RGMb; chicken; embryo; neural plate, neurogenesis; dorsal root ganglia; pharyngeal ectoderm; notochord; somite; dermomyotome; myotome Key findings:RGMa and RGMb expression patterns in neural tissues are conserved in gnathostome vertebrates. RGMa might be associated with muscle stem cells capable of undertaking myogenesis, and RGMb with cells ready to enter myogenic differentiation. Developmental DynamicsABBREVIATIONS asp anterior segmental plate di diencephalon dm dermomyotome dml dorsomedial lip of the dermomyotome drg dorsal root ganglion ect ectoderm edl Extensor Digitorum Longus end endoderm f fibula bone fge foregut endoderm fp floor plate of the neural tube hm head mesoderm hy hyoid (2nd) pharyngeal arch m myotome ma mandibular (1st) pharyngeal arch mes mesencephalon mx maxillary aspect of the 1st pharyngeal arch myel myelencephalon node Hensen's node (avian organizer) not notochord np neural plate nt neural tube op otic placode os optic stalk ov otic vesicle pa pharyngeal arch pchpl prechordal plate p/not posterior notochord ps primitive streak r1 r2 etc rhombomere 1 rhombomere 2 etc. s0 epithelializing somite s1 s5 etc 1st somite 5th somite etc. t tibiotarsal bone tel telencephalon V trigeminal (5th cranial nerve) ganglion VII facial (7th cranial nerve) ganglion vll ventromedial lip of the dermomyotome.Additional Supporting information may be found in the online version of this article.

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Section: Introductionmentioning

confidence: 81%

RGMa and RGMb expression pattern during chicken development suggest unexpected roles for these repulsive guidance molecules in notochord formation, somitogenesis, and myogenesis

Jorge

Ahmed

Bothe

et al. 2012

Developmental Dynamics

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“…For example, crosses between the highly polymorphic DA and PVG. AV1 rat strains, which demonstrate differential susceptibilities to EAE, have led to successful identification of several candidate genes that have also been translated as MS risk genes, including MHCIITA, VAV1, IL-21R, and CCL chemokines (13,(15)(16)(17). Importantly, congenic lines can be established for risk genes and thereby offer a tool in further studying their functional relevance.…”

Section: Ultiple Sclerosis (Ms) Is a Demyelinating Inflammatorymentioning

confidence: 99%

IL-22RA2 Associates with Multiple Sclerosis and Macrophage Effector Mechanisms in Experimental Neuroinflammation

Beyeen

Adzemovic

Öckinger

et al. 2010

The Journal of Immunology

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Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the CNS. Recent advances in whole-genome screening tools have enabled discovery of several MS risk genes, the majority of which have known immune-related functions. However, disease heterogeneity and low tissue accessibility hinder functional studies of established MS risk genes. For this reason, the MS model experimental autoimmune encephalomyelitis (EAE) is often used to study neuroinflammatory disease mechanisms. In this study, we performed high-resolution linkage analysis in a rat advanced intercross line to identify an EAE-regulating quantitative trait locus, Eae29, on rat chromosome 1. Eae29 alleles from the resistant strain both conferred milder EAE and lower production of proinflammatory molecules in macrophages, as demonstrated by the congenic line, DA.PVG-Eae29 (Dc1P). The soluble IL-22R α2 gene (Il-22ra2) lies within the Eae29 locus, and its expression was reduced in Dc1P, both in activated macrophages and splenocytes from immunized rats. Moreover, a single nucleotide polymorphism located at the end of IL-22RA2 associated with MS risk in a combined Swedish and Norwegian cohort comprising 5019 subjects, displaying an odds ratio of 1.26 (p = 8.0 × 10−4). IL-22 and its receptors have been implicated in chronic inflammation, suggesting that IL-22RA2 regulates a central immune pathway. Through a combined approach including genetic and immunological investigation in an animal model and large-scale association studies of MS patients, we establish IL-22RA2 as an MS risk gene.

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“…18 Additionally, RGMa has been considered a potential candidate gene in multiple sclerosis. 5,19 It is also found that inhibiting RGMa expression attenuates clinical signs and reduces neuronal damage in a specific Th17-induced EAE. 20 These lines of evidence all suggest a role for RGMa in immune regulation.…”

Section: Discussionmentioning

confidence: 99%

Repulsive guidance molecule a blockade exerts the immunoregulatory function in DCs stimulated with ABP and LPS

Gao

Zhai

et al. 2016

Human Vaccines & Immunotherapeutics

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Repulsive guidance molecule a (RGMa) is an axonal guidance molecule that has recently found to exert function in immune system. This study evaluated the function of RGMa in modulation of dendritic cells (DCs) function stimulated with Achyranthes bidentata polysaccharide (ABP) and lipopolysaccharide (LPS) using a RGMa-neutralizing antibody. Compared with the Control-IgG/ABP and Control-IgG/LPS groups, DCs in the Anti-RGMa/ABP and Anti-RGMa/LPS groups 1) showed small, round cells with a few cell processes and organelles, and many pinocytotic vesicles; 2) had decreased MHC II, CD86, CD80, and CD40 expression; 3) displayed the decreased IL-12p70, IL-1b and TNF-a levels and increased IL-10 secretion; 4) had a high percentage of FITC-dextran uptake; and 5) displayed a reduced ability to drive T cell proliferation and reinforced T cell polarization toward a Th2 cytokine pattern. We conclude that DCs treated with RGMa-neutralizing antibodies present with tolerogenic and immunoregulatory characteristics, which provides new insights into further understanding of the function of RGMa.

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RGMA and IL21R show association with experimental inflammation and multiple sclerosis

Cited by 61 publications

References 65 publications

RGMa and RGMb expression pattern during chicken development suggest unexpected roles for these repulsive guidance molecules in notochord formation, somitogenesis, and myogenesis

RGMa and RGMb expression pattern during chicken development suggest unexpected roles for these repulsive guidance molecules in notochord formation, somitogenesis, and myogenesis

IL-22RA2 Associates with Multiple Sclerosis and Macrophage Effector Mechanisms in Experimental Neuroinflammation

Repulsive guidance molecule a blockade exerts the immunoregulatory function in DCs stimulated with ABP and LPS

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