title: Repulsive guidance molecule-A (RGM-A) inhibits leukocyte migration and mitigates inflammation.
abstract: 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.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Tübingen University Hospital, 72076 Tübingen, Germany.
authors.forename: Valbona
authors.initials: V
authors.lastname: Mirakaj
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brown
authors.forename: Stefanie
authors.initials: S
authors.lastname: Laucher
authors.forename: Carolin
authors.initials: C
authors.lastname: Steinl
authors.forename: Gerd
authors.initials: G
authors.lastname: Klein
authors.forename: David
authors.initials: D
authors.lastname: Köhler
authors.forename: Thomas
authors.initials: T
authors.lastname: Skutella
authors.forename: Christian
authors.initials: C
authors.lastname: Meisel
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brommer
authors.forename: Peter
authors.initials: P
authors.lastname: Rosenberger
authors.forename: Jan M
authors.initials: JM
authors.lastname: Schwab
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002633:Chemotaxis / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D004848:Epithelium / Q000276:immunology / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D010538:Peritonitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015054:Zymosan / Q000633:toxicity
chemical_list: D016207:Cytokines; D058851:GPI-Linked Proteins; D009419:Nerve Tissue Proteins; C522183:RGMA protein, human; C483496:Rgma protein, mouse; D015054:Zymosan