Neogenin Signalling during Hypoxia, Inflammation and Ischemia-Reperfusion
Final Report Abstract
Treatment options for patients suffering from shock, sepsis or acute organ failure are sparse and expensive. A hallmark of these conditions is an inflammatory reaction with the infiltration of inflammatory cells into the affected tissue sites. Recent work has identified endogenous guidance cues that were originally described during axonal migration outside the nervous system and discovered their anti-inflammatory potential. The neogenin receptor (Neo1) is an important target receptor for these neuronal guidance proteins during axonal growth, yet its role during acute inflammation was to date unknown. In this project we found that Neo1 is significantly expressed and also induced during conditions associated with acute inflammation. Neo1 guides the migration of leukocytes, especially neutrophils during inflammation in-vitro and in-vivo. In addition, Neo1 induces the expression of inflammatory cytokines during the initiation of acute inflammation. We also report here that Neo1 does not directly influence the properties of endothelial barrier function in-vitro and invivo. During experiments in chimeric animals in-vivo we found that the observed results are confined to the hematopoietic Neo1 expression. As a result of this Neo1 deficient animals demonstrate reduced inflammatory organ changes in a model of sterile lung injury and zymosan induced peritonitis. Furthermore, we found that the endogenous ligand of Neo1, the repulsive guidance molecule A, inhibits leukocyte migration and dampens an acute inflammatory response in-vitro as well as in-vivo. Taken together, we have shown that Neo1 holds significant influence on the initiation of an inflammatory response and could be a target to reduce the detrimental effects of conditions associated with excessive inflammation in the future.
Publications
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Der Neogeninrezeptor als proinflammatorischer Mediator beim beatmungsinduzierten akuten Lungenschaden. Wissenschaftliche Arbeitstage der DGAI (WAT) Würzburg 2011 (DAC) Leipzig 2014
Mirakaj V
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Repulsive guidance molecule-A (RGM-A) inhibits leukocyte migration and mitigates inflammation. Proc Natl Acad Sci USA. 2011 Apr 19;108(16):6555-60
Mirakaj V, Brown S, Laucher S, Steinl C, Klein G, Köhler D, Skutella T, Meisel C, Brommer B, Rosenberger P, Schwab JM
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Der Neogeninrezeptor als proinflammatorischer Mediator bei akuter Peritonitis. Wissenschaftliche Arbeitstage der DGAI (WAT) Würzburg 2012
Mirakaj V
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The axonal guidance receptor neogenin promotes acute inflammation. PLoS One. 2012;7(3):e32145
König K, Gatidou D, Granja T, Meier J, Rosenberger P, Mirakaj V
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The guidance receptor neogenin promotes pulmonary inflammation during lung injury. FASEB J. 2012 Apr;26(4):1549-58
Mirakaj V, Jennewein C, König K, Granja T, Rosenberger P
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Vagus nerve controls resolution and pro-resolving mediators of inflammation. J Exp Med. 2014 Jun 2; 211(6):1037-48
Mirakaj V, Dalli J, Granja T, Rosenberger P, Serhan CN
