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.
Abstract-Extracellular ATP liberated during hypoxia and inflammation can either signal directly on purinergic receptors or can activate adenosine receptors following phosphohydrolysis to adenosine. Given the association of polymorphonuclear leukocytes (PMNs) with adenine-nucleotide/nucleoside signaling in the inflammatory milieu, we hypothesized that PMNs are a source of extracellular ATP. Initial studies using high-performance liquid chromatography and luminometric ATP detection assays revealed that PMNs release ATP through activation-dependent pathways.In vitro models of endothelial barrier function and neutrophil/endothelial adhesion indicated that PMN-derived ATP signals through endothelial adenosine receptors, thereby promoting endothelial barrier function and attenuating PMN/endothelial adhesion. Metabolism of extracellular ATP to adenosine required PMNs, and studies addressing these metabolic steps revealed that PMN express surface ecto-apyrase (CD39). In fact, studies with PMNs derived from cd39 Ϫ/Ϫ mice showed significantly increased levels of extracellular ATP and lack of ATP dissipation from their supernatants. After excluding lytic ATP release, we used pharmacological strategies to reveal a potential mechanism involved in PMN-dependent ATP release (eg, verapamil, dipyridamole, brefeldin A, 18-␣-glycyrrhetinic acid, connexin-mimetic peptides). These studies showed that PMN ATP release occurs through connexin 43 (Cx43) hemichannels in a protein/phosphatase-A-dependent manner. Findings in human PMNs were confirmed in PMNs derived from induced Cx43 Ϫ/Ϫ mice, whereby activated PMNs release less than 15% of ATP relative to littermate controls, whereas Cx43 heterozygote PMNs were intermediate in their capacity for ATP release (PϽ0.01). Taken together, our results identify a previously unappreciated role for Cx43 in activated PMN ATP release, therein contributing to the innate metabolic control of the inflammatory milieu. (Circ Res. 2006;99:1100-1108.) Key Words: nucleotide Ⅲ nucleoside Ⅲ adenosine Ⅲ endothelia Ⅲ inflammation Ⅲ ATP Ⅲ connexin Ⅲ inflammation Ⅲ hypoxia P ast studies have revealed a central role of extracellular nucleotide phosphohydrolysis and nucleoside signaling in innate immune responses during conditions of limited oxygen availability (hypoxia) or during acute inflammation. For example, metabolic enzymes and vascular nucleotide levels are consistently increased during hypoxia. 1,2 The contribution of individual nucleotides (ATP, ADP, AMP) to these innate responses remain unclear. Polymorphonuclear granulocytes (PMNs) function as a first line of cellular response during acute inflammatory episodes. 3 Previous reports have suggested that PMNs may release ATP during conditions of inflammation or hypoxia. 1 Such extracellular ATP can either signal directly to vascular ATP receptors 4 or may function as a metabolite following conversion via ecto-apyrase (CD39, conversion of ATP to AMP) and ecto-5Ј-nucleotidase (CD73, conversion of AMP to adenosine).In the present study, we aimed to identify mol...
Interactions between the vascular endothelium and polymorphonuclear leukocytes (PMNs) are central to PMN emigration into inflamed tissues, and to neutrophil-endothelial crosstalk pathways that modulate inflammatory responses and vascular barrier function. For example, during episodes of inflammation, the transendothelial migration (TEM) of PMNs potentially disturbs vascular barrier and gives rise to intravascular fluid extravasation and edema. However, because of the close special relationship between PMNs and the vascular endothelium, TEM creates an ideal situation for neutrophil-endothelial crosstalk. While investigating innate mechanisms to dampen intravascular fluid loss and edema occurring during TEM, we observed that PMNs release adenine nucleotides after activation (adenosine triphosphate [ATP] and adenosine monophosphate [AMP]). ATP and AMP are metabolized by endothelial cell-surface enzymes, the ecto-apyrase (CD39, metabolizes ATP to AMP) and the 5'-ecto-nucleotidase (CD73, metabolizes AMP to adenosine). Adenosine generated in this fashion can activate endothelial adenosine receptors, leading to increases in intracellular cyclic AMP and resealing of the endothelial junctions, thereby promoting vascular barrier function. This crosstalk pathway provides an endogenous mechanism to dampen vascular leak syndrome during neutrophil-endothelial interaction. In other words, during TEM, neutrophils close the door behind them.
Introduction:In this study, we evaluated the role of the Netrin-1 receptor UNC5b (Uncoordinated), a neuronal guidance molecule, during peripheral nerve regeneration using the mouse median nerve model. Materials and methods: Using Western blot analysis, we examined the expression changes of UNC5b after transection and microsurgical repair of the mouse median nerve distal to the transection site. We evaluated the histomorphometrical changes and functional recovery of the grasping force after median nerve transection and repair in wild-type (WT) mice and UNC5b þ/2 heterozygous mice.
In the version of this article initially published, the contrast in lane 4 of Figure 2c had been altered, and the top right image in Figure 5a and bottom right image Figure 6e were incorrect. The correct gel and images are now presented. The error has been corrected in the HTML and PDF versions of the article.Corrigendum: A new class of highly potent, broadly neutralizing antibodies isolated from viremic patients infected with dengue virus In the version of this article initially published, the sixth author's surname is spelled incorrectly. The correct spelling is Rouvinski. The error has been corrected in the HTML and PDF versions of the article. In the version of this article initially published, the Acknowledgments section was incomplete. The correct text should begin "We thank P. O'Brien, M. Mochizuki and N. Takeno for assistance with tissue collection.... " The error has been corrected in the HTML and PDF versions of the article. 544
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