| Repulsive guidance molecule-A (RGM-A) inhibits leukocyte migration and mitigates inflammation. | |
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MedLine Citation:
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PMID: 21467223 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Directed cell migration is a prerequisite not only for the development of the central nervous system, but also for topically restricted, appropriate immune responses. This is crucial for host defense and immune surveillance. Attracting environmental cues guiding leukocyte cell traffic are likely to be complemented by repulsive cues, which actively abolish cell migration. One such a paradigm exists in the developing nervous system, where neuronal migration and axonal path finding is balanced by chemoattractive and chemorepulsive cues, such as the neuronal repulsive guidance molecule-A (RGM-A). As expressed at the inflammatory site, the role of RGM-A within the immune response remains unclear. Here we report that RGM-A (i) is expressed by epithelium and leukocytes (granulocytes, monocytes, and T/B lymphocytes); (ii) inhibits leukocyte migration by contact repulsion and chemorepulsion, depending on dosage, through its receptor neogenin; and (iii) suppresses the inflammatory response in a model of zymosan-A-induced peritonitis. Systemic application of RGM-A attenuates the humoral proinflammatory response (TNF-α, IL-6, and macrophage inflammatory protein 1α), infiltration of inflammatory cell traffic, and edema formation. In contrast, the demonstrated anti-inflammatory effect of RGM-A is absent in mice homozygous for a gene trap mutation in the neo1 locus (encoding neogenin). Thus, our results suggest that RGM-A is a unique endogenous inhibitor of leukocyte chemotaxis that limits inflammatory leukocyte traffic and creates opportunities to better understand and treat pathologies caused by exacerbated or misdirected inflammatory responses. |
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Authors:
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Valbona Mirakaj; Sebastian Brown; Stefanie Laucher; Carolin Steinl; Gerd Klein; David Köhler; Thomas Skutella; Christian Meisel; Benedikt Brommer; Peter Rosenberger; Jan M Schwab |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2011-04-05 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 108 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-04-20 Completed Date: 2011-06-17 Revised Date: 2011-10-19 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 6555-60 Citation Subset: IM |
Affiliation:
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Department of Anesthesiology and Intensive Care Medicine, Tübingen University Hospital, 72076 Tübingen, Germany. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Caco-2 Cells Chemotaxis / drug effects, genetics, immunology* Cytokines / biosynthesis, genetics, immunology Epithelium / immunology, metabolism GPI-Linked Proteins / biosynthesis, genetics, immunology Gene Expression Regulation / drug effects, genetics, immunology* Humans Inflammation / chemically induced, genetics, immunology, metabolism Leukocytes / immunology*, metabolism Mice Mice, Knockout Nerve Tissue Proteins / biosynthesis, genetics, immunology* Organ Specificity / drug effects, genetics, immunology Peritonitis / chemically induced, genetics, immunology*, metabolism Zymosan / toxicity |
| Chemical | |
Reg. No./Substance:
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0/Cytokines; 0/GPI-Linked Proteins; 0/Nerve Tissue Proteins; 0/RGMA protein, human; 0/Rgma protein, mouse; 9010-72-4/Zymosan |
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