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Holger K Eltzschig - One of the best experts on this subject based on the ideXlab platform.
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neuronal guidance molecule Netrin 1 attenuates inflammatory cell trafficking during acute experimental colitis
Gut, 2012Co-Authors: Carol M Aherne, Colm B Collins, Joanne C Masterson, Marco Tizzano, Theresa A Boyle, Joseph A Westrich, Jason A Parnes, Glenn T Furuta, Jesus Riveranieves, Holger K EltzschigAbstract:Background Inflammatory bowel diseases, encompassing Crohn9s disease and ulcerative colitis, are characterised by persistent leucocyte tissue infiltration leading to perpetuation of an inappropriate inflammatory cascade. The neuronal guidance molecule Netrin-1 has recently been implicated in the orchestration of leucocyte trafficking during acute inflammation. We therefore hypothesised that Netrin-1 could modulate leucocyte infiltration and disease activity in a model of inflammatory bowel disease. Design DSS-colitis was performed in mice with partial genetic Netrin-1 deficiency ( Ntn-1 +/− mice) or wild-type mice treated with exogenous Netrin-1 via osmotic pump to examine the role of endogenous and therapeutically administered Netrin-1. These studies were supported by in vitro models of transepithelial migration and intestinal epithelial barrier function. Results Consistent with our hypothesis, we observed induction of Netrin-1 during intestinal inflammation in vitro or in mice exposed to experimental colitis. Moreover, mice with partial Netrin-1 deficiency demonstrated an exacerbated course of DSS-colitis compared to littermate controls, with enhanced weight loss and colonic shortening. Conversely, mice treated with exogenous mouse Netrin-1 experienced attenuated disease severity. Importantly, permeability studies and quantitative assessment of apoptosis reveal that Netrin-1 signalling events do not alter mucosal permeability or intestinal epithelial cell apoptosis. In vivo studies of leucocyte transmigration demonstrate suppression of neutrophil trafficking as a key function mediated by endogenous or exogenously administered Netrin-1. Finally, genetic studies implicate the A2B adenosine receptor in Netrin-1-mediated protection during DSS-colitis. Conclusions The present study identifies a previously unrecognised role for Netrin-1 in attenuating experimental colitis through limitation of neutrophil trafficking.
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hypoxia inducible factor dependent induction of Netrin 1 dampens inflammation caused by hypoxia
Nature Immunology, 2009Co-Authors: Peter Rosenberger, Holger K Eltzschig, Valbona Mirakaj, Julio C Morotegarcia, Klaus Unertl, Jan M Schwab, Eva Masekowsky, Alice MagerAbstract:The neuronal guidance molecule Netrin-1 is linked to the coordination of inflammatory responses. Given that mucosal surfaces are particularly prone to hypoxia-elicited inflammation, we sought to determine the function of Netrin-1 in hypoxia-induced inflammation. We detected hypoxia-inducible factor 1alpha (HIF-1alpha)-dependent induction of expression of the gene encoding Netrin-1 (Ntn1) in hypoxic epithelia. Neutrophil transepithelial migration studies showed that by engaging A2B adenosine receptor (A2BAR) on neutrophils, Netrin-1 attenuated neutrophil transmigration. Exogenous Netrin-1 suppressed hypoxia-elicited inflammation in wild-type but not in A2BAR-deficient mice, and inflammatory hypoxia was enhanced in Ntn1(+/-) mice relative to that in Ntn1(+/+) mice. Our studies demonstrate that HIF-1alpha-dependent induction of Netrin-1 attenuates hypoxia-elicited inflammation at mucosal surfaces.
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hypoxia inducible factor dependent induction of Netrin 1 dampens inflammation caused by hypoxia
Nature Immunology, 2009Co-Authors: Peter Rosenberger, Holger K Eltzschig, Valbona Mirakaj, Julio C Morotegarcia, Klaus Unertl, Jan M Schwab, Eva Masekowsky, Alice MagerAbstract:Hypoxia incites inflammation, particularly at mucosal surfaces. Eltzschig and colleagues show that hypoxia also suppresses inflammation by inducing expression of the neuronal guidance molecule Netrin-1, which inhibits the transepithelial migration of neutrophils. The neuronal guidance molecule Netrin-1 is linked to the coordination of inflammatory responses. Given that mucosal surfaces are particularly prone to hypoxia-elicited inflammation, we sought to determine the function of Netrin-1 in hypoxia-induced inflammation. We detected hypoxia-inducible factor 1α (HIF-1α)-dependent induction of expression of the gene encoding Netrin-1 (Ntn1) in hypoxic epithelia. Neutrophil transepithelial migration studies showed that by engaging A2B adenosine receptor (A2BAR) on neutrophils, Netrin-1 attenuated neutrophil transmigration. Exogenous Netrin-1 suppressed hypoxia-elicited inflammation in wild-type but not in A2BAR-deficient mice, and inflammatory hypoxia was enhanced in Ntn1+/− mice relative to that in Ntn1+/+ mice. Our studies demonstrate that HIF-1α-dependent induction of Netrin-1 attenuates hypoxia-elicited inflammation at mucosal surfaces.
Patrick Mehlen - One of the best experts on this subject based on the ideXlab platform.
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Netrin 1 and its receptor dcc modulate survival and death of dopamine neurons and parkinson s disease features
The EMBO Journal, 2021Co-Authors: Melissa Jasmin, Seong Su Kang, Eun Hee Ahn, Merja H Voutilainen, Joanna Fombonne, Catherine Guix, Tuulikki Viljakainen, Mart Saarma, Patrick MehlenAbstract:The Netrin-1/DCC ligand/receptor pair has key roles in central nervous system (CNS) development, mediating axonal, and neuronal navigation. Although expression of Netrin-1 and DCC is maintained in the adult brain, little is known about their role in mature neurons. Notably, Netrin-1 is highly expressed in the adult substantia nigra, leading us to investigate a role of the Netrin-1/DCC pair in adult nigral neuron fate. Here, we show that silencing Netrin-1 in the adult substantia nigra of mice induces DCC cleavage and a significant loss of dopamine neurons, resulting in motor deficits. Because loss of adult dopamine neurons and motor impairments are features of Parkinson's disease (PD), we studied the potential impact of Netrin-1 in different animal models of PD. We demonstrate that both overexpression of Netrin-1 and brain administration of recombinant Netrin-1 are neuroprotective and neurorestorative in mouse and rat models of PD. Of interest, we observed that Netrin-1 levels are significantly reduced in PD patient brain samples. These results highlight the key role of Netrin-1 in adult dopamine neuron fate, and the therapeutic potential of targeting Netrin-1 signaling in PD.
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Ultrasound molecular imaging as a non-invasive companion diagnostic for Netrin-1 interference therapy in breast cancer
Theranostics, 2018Co-Authors: Jennifer Wischhusen, Rodolfo Molina-peña, Jacqueline Ngo, Benoit Gibert, Jean Guy Delcros, David Goldschneider, Patrick Mehlen, Katheryne E. Wilson, Shan Jiang, Juergen K WillmannAbstract:In ultrasound molecular imaging (USMI), ligand-functionalized microbubbles (MBs) are used to visualize vascular endothelial targets. Netrin-1 is upregulated in 60% of metastatic breast cancers and promotes tumor progression. A novel Netrin-1 interference therapy requires the assessment of Netrin-1 expression prior to treatment. In this study, we studied Netrin-1 as a target for USMI and its potential as a companion diagnostic in breast cancer models. Methods: To verify Netrin-1 expression and localization, an in vivo immuno-localization approach was applied, in which anti-Netrin-1 antibody was injected into living mice 24 h before tumor collection, and revealed with secondary fluorescent antibody for immunofluorescence analysis. Netrin-1 interactions with the cell surface were studied by flow cytometry. Netrin-1-targeted MBs were prepared using MicroMarker Target-Ready (VisualSonics), and validated in in vitro binding assays in static conditions or in a flow chamber using purified Netrin-1 protein or Netrin-1-expressing cancer cells. In vivo USMI of Netrin-1 was validated in nude mice bearing human Netrin-1-positive SKBR7 tumors or weakly Netrin-1-expressing MDA-MB-231 tumors using the Vevo 2100 small animal imaging device (VisualSonics). USMI feasibility was further tested in transgenic murine FVB/N Tg(MMTV/PyMT634Mul) (MMTV-PyMT) mammary tumors. Results: Netrin-1 co-localized with endothelial CD31 in Netrin-1-positive breast tumors. Netrin-1 binding to the surface of endothelial HUVEC and cancer cells was partially mediated by heparan sulfate proteoglycans. MBs targeted with humanized monoclonal anti-Netrin-1 antibody bound to Netrin-1-expressing cancer cells in static and dynamic conditions. USMI signal was significantly increased with anti-Netrin-1 MBs in human SKBR7 breast tumors and transgenic murine MMTV-PyMT mammary tumors compared to signals recorded with either isotype control MBs or after blocking of Netrin-1 with humanized monoclonal anti-Netrin-1 antibody. In weakly Netrin-1-expressing human tumors and normal mammary glands, no difference in imaging signal was observed with anti-Netrin-1- and isotype control MBs. Ex vivo analysis confirmed Netrin-1 expression in MMTV-PyMT tumors. Conclusions: These results show that USMI allowed reliable detection of Netrin-1 on the endothelium of Netrin-1-positive human and murine tumors. Significant differences in USMI signal for Netrin-1 reflected the significant differences in Netrin-1 mRNA & protein expression observed between different breast tumor models. The imaging approach was non-invasive and safe, and provided the Netrin-1 expression status in near real-time. Thus, USMI of Netrin-1 has the potential to become a companion diagnostic for the stratification of patients for Netrin-1 interference therapy in future clinical trials.
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Netrin 1 overexpression protects kidney from ischemia reperfusion injury by suppressing apoptosis
American Journal of Pathology, 2009Co-Authors: Weiwei Wang, Patrick Mehlen, Laurent Pays, William Brian Reeves, Ganesan RameshAbstract:Netrin-1, a diffusible laminin-related protein, is highly expressed in the kidney. However, the pathophysiological roles of Netrin-1 in the kidney are unknown. To address this question directly, we used transgenic mice that overexpress chicken Netrin-1 in the kidney. Netrin-1 overexpression was confirmed by real-time RT-PCR and Western blot analysis. Eight-week-old wild-type and transgenic mice were subjected to 26 minutes of renal ischemia followed by reperfusion for 72 hours. Wild-type mice developed more severe renal dysfunction by 24 hours than Netrin-1 transgenic mice. Functional improvement was associated with better preservation of morphology, reduced cytokine expression, and reduced oxidative stress in the kidney of transgenic mice as compared with wild-type mice. In addition, both basal and reperfusion-induced cell proliferation were dramatically increased in transgenic kidneys as determined by Ki-67 staining. Interestingly, ischemia reperfusion induced a large increase in apoptosis in wild-type mice but not in Netrin-1 transgenic mice that was associated with reduced caspase-3 activation in the transgenic kidney. These results suggest that Netrin-1 protects renal tubular epithelial cells against ischemia reperfusion-induced injury by increasing proliferation and suppressing apoptosis.
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Inhibition of endothelial cell apoptosis by Netrin-1 during angiogenesis
Developmental Cell, 2009Co-Authors: Marie Castets, Jean Guy Delcros, Mariemay Coissieux, Agnes Bernet, Céline Delloye-bourgeois, Laure Bernard, Vincent Laudet, Patrick MehlenAbstract:Netrin-1 was recently proposed to play an important role in embryonic and pathological angiogenesis. However, data reported led to the apparently contradictory conclusions that Netrin-1 is either a pro- or an antiangiogenic factor. Here, we reconcile these opposing observations by demonstrating that Netrin-1 acts as a survival factor for endothelial cells, blocking the proapoptotic effect of the dependence receptor UNC5B and its downstream death signaling effector, the serine/threonine kinase DAPK. The Netrin-1 effect on blood vessel development is mimicked by caspase inhibitors in ex vivo assays, and the inhibition of caspase activity, the silencing of the UNC5B receptor, and the silencing of DAPK are each sufficient to rescue the vascular sprouting defects induced by Netrin-1 silencing in zebrafish. Thus, the proapoptotic effect of unbound UNC5B, and the survival effect of Netrin-1 on endothelial cells finely tune the angiogenic process.
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Netrin 1 is a survival factor during commissural neuron navigation
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Celine Furne, Veronique Corset, A. Chedotal, Nicolas Rama, Patrick MehlenAbstract:DCC (Deleted in Colorectal Cancer) is a putative tumor suppressor whose expression is lost in numerous cancers and whose tumor suppressor activity appears to be dependent on its ability to trigger apoptosis when disengaged by its ligand Netrin-1. In this sense, Netrin-1 is a survival factor that controls tumorigenesis. However, Netrin-1 is also the prototypical axon guidance cue and has been shown to orient many neurons or axons, especially commissural axons, during spinal cord development. Here we show that Netrin-1 is not only an attractive cue for developing commissural axons but also promotes their survival. In primary neuronal culture, in mice or in chick embryos, Netrin-1 inhibits the proapoptotic activity of DCC in developing commissural neurons. Thus, adequate commissural neurons navigation requires both the attractive activity of Netrin-1 and the anti-apoptotic function of this cue.
Peter Rosenberger - One of the best experts on this subject based on the ideXlab platform.
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Netrin 1 dampens pulmonary inflammation during acute lung injury
American Journal of Respiratory and Critical Care Medicine, 2010Co-Authors: Valbona Mirakaj, Cyril A Thix, Stefanie Laucher, Carina Mielke, Julio C Morotegarcia, Marthe A Schmit, Janek Henes, Klaus Unertl, David Kohler, Peter RosenbergerAbstract:Rationale: Acute lung injury (ALI) is an inflammatory disorder characterized by hypoxemia and diffuse infiltration of neutrophils into the alveolar space. The migration and extravasation of neutrophils is guided through positive guidance cues, such as chemokines. Recent work has identified the neuronal guidance protein Netrin-1 to be a negative guidance cue for leukocyte migration and to hold antiinflammatory potential.Objectives: To test the role of pulmonary Netrin-1 during ALI.Methods: Pulmonary Netrin-1 expression was evaluated during acute inflammation in vitro and in vivo; the Netrin-1 promoter was studied using pGL4 luciferase reporter. ALI was induced through LPS inhalation and mechanical ventilation in wild-type, Ntn1+/−, and A2BAR−/− animals. Exogenous Netrin-1 was used to evaluate its impact on pulmonary inflammation.Measurements and Main Results: Wild-type animals demonstrated repression of pulmonary Netrin-1 after LPS inhalation. In vitro studies confirmed the repression of Netrin-1. Studies ...
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hypoxia inducible factor dependent induction of Netrin 1 dampens inflammation caused by hypoxia
Nature Immunology, 2009Co-Authors: Peter Rosenberger, Holger K Eltzschig, Valbona Mirakaj, Julio C Morotegarcia, Klaus Unertl, Jan M Schwab, Eva Masekowsky, Alice MagerAbstract:The neuronal guidance molecule Netrin-1 is linked to the coordination of inflammatory responses. Given that mucosal surfaces are particularly prone to hypoxia-elicited inflammation, we sought to determine the function of Netrin-1 in hypoxia-induced inflammation. We detected hypoxia-inducible factor 1alpha (HIF-1alpha)-dependent induction of expression of the gene encoding Netrin-1 (Ntn1) in hypoxic epithelia. Neutrophil transepithelial migration studies showed that by engaging A2B adenosine receptor (A2BAR) on neutrophils, Netrin-1 attenuated neutrophil transmigration. Exogenous Netrin-1 suppressed hypoxia-elicited inflammation in wild-type but not in A2BAR-deficient mice, and inflammatory hypoxia was enhanced in Ntn1(+/-) mice relative to that in Ntn1(+/+) mice. Our studies demonstrate that HIF-1alpha-dependent induction of Netrin-1 attenuates hypoxia-elicited inflammation at mucosal surfaces.
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hypoxia inducible factor dependent induction of Netrin 1 dampens inflammation caused by hypoxia
Nature Immunology, 2009Co-Authors: Peter Rosenberger, Holger K Eltzschig, Valbona Mirakaj, Julio C Morotegarcia, Klaus Unertl, Jan M Schwab, Eva Masekowsky, Alice MagerAbstract:Hypoxia incites inflammation, particularly at mucosal surfaces. Eltzschig and colleagues show that hypoxia also suppresses inflammation by inducing expression of the neuronal guidance molecule Netrin-1, which inhibits the transepithelial migration of neutrophils. The neuronal guidance molecule Netrin-1 is linked to the coordination of inflammatory responses. Given that mucosal surfaces are particularly prone to hypoxia-elicited inflammation, we sought to determine the function of Netrin-1 in hypoxia-induced inflammation. We detected hypoxia-inducible factor 1α (HIF-1α)-dependent induction of expression of the gene encoding Netrin-1 (Ntn1) in hypoxic epithelia. Neutrophil transepithelial migration studies showed that by engaging A2B adenosine receptor (A2BAR) on neutrophils, Netrin-1 attenuated neutrophil transmigration. Exogenous Netrin-1 suppressed hypoxia-elicited inflammation in wild-type but not in A2BAR-deficient mice, and inflammatory hypoxia was enhanced in Ntn1+/− mice relative to that in Ntn1+/+ mice. Our studies demonstrate that HIF-1α-dependent induction of Netrin-1 attenuates hypoxia-elicited inflammation at mucosal surfaces.
Valbona Mirakaj - One of the best experts on this subject based on the ideXlab platform.
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the neuroimmune guidance cue Netrin 1 controls resolution programs and promotes liver regeneration
Hepatology, 2016Co-Authors: Martin Schlegel, David Kohler, Andreas Korner, Tiago Granja, Andreas Straub, Martin Giera, Valbona MirakajAbstract:Hepatic ischemia/reperfusion (I/R) is a major adverse reaction to liver transplantation, hemorrhagic shock, or resection. Recently, the anti-inflammatory properties of the axonal guidance cue Netrin-1 were reported. Here, we demonstrate that Netrin-1 also impacts the resolution of inflammation and promotes hepatic repair and regeneration during liver I/R injury. In initial studies, we investigated the induction of Netrin-1 and its receptors in murine liver tissues after I/R injury. Hepatic I/R injury was performed in mice with a partial genetic Netrin-1 deficiency (Ntn1+/−) or wild-type C57BL/6 treated with exogenous Netrin-1 to examine the endogenous and therapeutically administered impact of Netrin-1. These investigations were corroborated by studies determining the characteristics of intravascular leukocyte flow, clearance of apoptotic neutrophils (polymorphonuclear cells [PMNs]), production of specialized proresolving lipid mediators (SPMs), generation of specific growth factors contributing to the resolution of inflammation, and liver repair. Hepatic I/R was associated with a significant reduction of Netrin-1 transcript and protein in murine liver tissue. Subsequent studies in Netrin-1-deficient mice revealed lower efficacies in reducing PMN infiltration, proinflammatory cytokine levels, and hepatic-specific injury enzymes. Conversely, mice treated with exogenous Netrin-1 exhibited increased liver protection and repair, reducing neutrophil influx into the injury site, decreasing proinflammatory mediators, increasing efferocytosis of apoptotic PMNs, and stimulating local endogenous biosynthesis of SPMs and the generation of specific growth factors. Finally, genetic studies implicated the A2B adenosine receptor in Netrin-1-mediated protection during hepatic I/R injury. Conclusion: The present study indicates a previously unrecognized role for Netrin-1 in liver protection and its contribution to tissue homeostasis and regeneration. (Hepatology 2016;63:1689-1705)
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Netrin 1 dampens pulmonary inflammation during acute lung injury
American Journal of Respiratory and Critical Care Medicine, 2010Co-Authors: Valbona Mirakaj, Cyril A Thix, Stefanie Laucher, Carina Mielke, Julio C Morotegarcia, Marthe A Schmit, Janek Henes, Klaus Unertl, David Kohler, Peter RosenbergerAbstract:Rationale: Acute lung injury (ALI) is an inflammatory disorder characterized by hypoxemia and diffuse infiltration of neutrophils into the alveolar space. The migration and extravasation of neutrophils is guided through positive guidance cues, such as chemokines. Recent work has identified the neuronal guidance protein Netrin-1 to be a negative guidance cue for leukocyte migration and to hold antiinflammatory potential.Objectives: To test the role of pulmonary Netrin-1 during ALI.Methods: Pulmonary Netrin-1 expression was evaluated during acute inflammation in vitro and in vivo; the Netrin-1 promoter was studied using pGL4 luciferase reporter. ALI was induced through LPS inhalation and mechanical ventilation in wild-type, Ntn1+/−, and A2BAR−/− animals. Exogenous Netrin-1 was used to evaluate its impact on pulmonary inflammation.Measurements and Main Results: Wild-type animals demonstrated repression of pulmonary Netrin-1 after LPS inhalation. In vitro studies confirmed the repression of Netrin-1. Studies ...
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hypoxia inducible factor dependent induction of Netrin 1 dampens inflammation caused by hypoxia
Nature Immunology, 2009Co-Authors: Peter Rosenberger, Holger K Eltzschig, Valbona Mirakaj, Julio C Morotegarcia, Klaus Unertl, Jan M Schwab, Eva Masekowsky, Alice MagerAbstract:The neuronal guidance molecule Netrin-1 is linked to the coordination of inflammatory responses. Given that mucosal surfaces are particularly prone to hypoxia-elicited inflammation, we sought to determine the function of Netrin-1 in hypoxia-induced inflammation. We detected hypoxia-inducible factor 1alpha (HIF-1alpha)-dependent induction of expression of the gene encoding Netrin-1 (Ntn1) in hypoxic epithelia. Neutrophil transepithelial migration studies showed that by engaging A2B adenosine receptor (A2BAR) on neutrophils, Netrin-1 attenuated neutrophil transmigration. Exogenous Netrin-1 suppressed hypoxia-elicited inflammation in wild-type but not in A2BAR-deficient mice, and inflammatory hypoxia was enhanced in Ntn1(+/-) mice relative to that in Ntn1(+/+) mice. Our studies demonstrate that HIF-1alpha-dependent induction of Netrin-1 attenuates hypoxia-elicited inflammation at mucosal surfaces.
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hypoxia inducible factor dependent induction of Netrin 1 dampens inflammation caused by hypoxia
Nature Immunology, 2009Co-Authors: Peter Rosenberger, Holger K Eltzschig, Valbona Mirakaj, Julio C Morotegarcia, Klaus Unertl, Jan M Schwab, Eva Masekowsky, Alice MagerAbstract:Hypoxia incites inflammation, particularly at mucosal surfaces. Eltzschig and colleagues show that hypoxia also suppresses inflammation by inducing expression of the neuronal guidance molecule Netrin-1, which inhibits the transepithelial migration of neutrophils. The neuronal guidance molecule Netrin-1 is linked to the coordination of inflammatory responses. Given that mucosal surfaces are particularly prone to hypoxia-elicited inflammation, we sought to determine the function of Netrin-1 in hypoxia-induced inflammation. We detected hypoxia-inducible factor 1α (HIF-1α)-dependent induction of expression of the gene encoding Netrin-1 (Ntn1) in hypoxic epithelia. Neutrophil transepithelial migration studies showed that by engaging A2B adenosine receptor (A2BAR) on neutrophils, Netrin-1 attenuated neutrophil transmigration. Exogenous Netrin-1 suppressed hypoxia-elicited inflammation in wild-type but not in A2BAR-deficient mice, and inflammatory hypoxia was enhanced in Ntn1+/− mice relative to that in Ntn1+/+ mice. Our studies demonstrate that HIF-1α-dependent induction of Netrin-1 attenuates hypoxia-elicited inflammation at mucosal surfaces.
Julio C Morotegarcia - One of the best experts on this subject based on the ideXlab platform.
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Netrin 1 dampens pulmonary inflammation during acute lung injury
American Journal of Respiratory and Critical Care Medicine, 2010Co-Authors: Valbona Mirakaj, Cyril A Thix, Stefanie Laucher, Carina Mielke, Julio C Morotegarcia, Marthe A Schmit, Janek Henes, Klaus Unertl, David Kohler, Peter RosenbergerAbstract:Rationale: Acute lung injury (ALI) is an inflammatory disorder characterized by hypoxemia and diffuse infiltration of neutrophils into the alveolar space. The migration and extravasation of neutrophils is guided through positive guidance cues, such as chemokines. Recent work has identified the neuronal guidance protein Netrin-1 to be a negative guidance cue for leukocyte migration and to hold antiinflammatory potential.Objectives: To test the role of pulmonary Netrin-1 during ALI.Methods: Pulmonary Netrin-1 expression was evaluated during acute inflammation in vitro and in vivo; the Netrin-1 promoter was studied using pGL4 luciferase reporter. ALI was induced through LPS inhalation and mechanical ventilation in wild-type, Ntn1+/−, and A2BAR−/− animals. Exogenous Netrin-1 was used to evaluate its impact on pulmonary inflammation.Measurements and Main Results: Wild-type animals demonstrated repression of pulmonary Netrin-1 after LPS inhalation. In vitro studies confirmed the repression of Netrin-1. Studies ...
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hypoxia inducible factor dependent induction of Netrin 1 dampens inflammation caused by hypoxia
Nature Immunology, 2009Co-Authors: Peter Rosenberger, Holger K Eltzschig, Valbona Mirakaj, Julio C Morotegarcia, Klaus Unertl, Jan M Schwab, Eva Masekowsky, Alice MagerAbstract:The neuronal guidance molecule Netrin-1 is linked to the coordination of inflammatory responses. Given that mucosal surfaces are particularly prone to hypoxia-elicited inflammation, we sought to determine the function of Netrin-1 in hypoxia-induced inflammation. We detected hypoxia-inducible factor 1alpha (HIF-1alpha)-dependent induction of expression of the gene encoding Netrin-1 (Ntn1) in hypoxic epithelia. Neutrophil transepithelial migration studies showed that by engaging A2B adenosine receptor (A2BAR) on neutrophils, Netrin-1 attenuated neutrophil transmigration. Exogenous Netrin-1 suppressed hypoxia-elicited inflammation in wild-type but not in A2BAR-deficient mice, and inflammatory hypoxia was enhanced in Ntn1(+/-) mice relative to that in Ntn1(+/+) mice. Our studies demonstrate that HIF-1alpha-dependent induction of Netrin-1 attenuates hypoxia-elicited inflammation at mucosal surfaces.
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hypoxia inducible factor dependent induction of Netrin 1 dampens inflammation caused by hypoxia
Nature Immunology, 2009Co-Authors: Peter Rosenberger, Holger K Eltzschig, Valbona Mirakaj, Julio C Morotegarcia, Klaus Unertl, Jan M Schwab, Eva Masekowsky, Alice MagerAbstract:Hypoxia incites inflammation, particularly at mucosal surfaces. Eltzschig and colleagues show that hypoxia also suppresses inflammation by inducing expression of the neuronal guidance molecule Netrin-1, which inhibits the transepithelial migration of neutrophils. The neuronal guidance molecule Netrin-1 is linked to the coordination of inflammatory responses. Given that mucosal surfaces are particularly prone to hypoxia-elicited inflammation, we sought to determine the function of Netrin-1 in hypoxia-induced inflammation. We detected hypoxia-inducible factor 1α (HIF-1α)-dependent induction of expression of the gene encoding Netrin-1 (Ntn1) in hypoxic epithelia. Neutrophil transepithelial migration studies showed that by engaging A2B adenosine receptor (A2BAR) on neutrophils, Netrin-1 attenuated neutrophil transmigration. Exogenous Netrin-1 suppressed hypoxia-elicited inflammation in wild-type but not in A2BAR-deficient mice, and inflammatory hypoxia was enhanced in Ntn1+/− mice relative to that in Ntn1+/+ mice. Our studies demonstrate that HIF-1α-dependent induction of Netrin-1 attenuates hypoxia-elicited inflammation at mucosal surfaces.