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      A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish

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          Abstract

          Barrier structures (e.g. epithelia around tissues, plasma membranes around cells) are required for internal homeostasis and protection from pathogens. Wound detection and healing represent a dormant morphogenetic program that can be rapidly executed to restore barrier integrity and tissue homeostasis. In animals, initial steps include recruitment of leukocytes to the site of injury across distances of hundreds of micrometers within minutes of wounding. The spatial signals that direct this immediate tissue response are unknown.

          Due to their fast diffusion and versatile biological activities, reactive oxygen species (ROS), including hydrogen peroxide (H 2O 2), are interesting candidates for wound-to-leukocyte signalling. We probed the role of H 2O 2 during the early events of wound responses in zebrafish larvae expressing a genetically encoded H 2O 2 sensor 1. This reporter revealed a sustained rise in H 2O 2 concentration at the wound margin, starting ∼3 min after wounding and peaking at ∼20 min, which extended ∼100−200 μm into the tail fin epithelium as a decreasing concentration gradient. Using pharmacological and genetic inhibition, we show that this gradient is created by Dual oxidase (Duox), and that it is required for rapid recruitment of leukocytes to the wound. This is the first observation of a tissue-scale H 2O 2 pattern, and the first evidence that H 2O 2 signals to leukocytes in tissues, in addition to its known antiseptic role.

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          Most cited references 24

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          The zebrafish lysozyme C promoter drives myeloid-specific expression in transgenic fish

          Background How different immune cell compartments contribute to a successful immune response is central to fully understanding the mechanisms behind normal processes such as tissue repair and the pathology of inflammatory diseases. However, the ability to observe and characterize such interactions, in real-time, within a living vertebrate has proved elusive. Recently, the zebrafish has been exploited to model aspects of human disease and to study specific immune cell compartments using fluorescent reporter transgenic lines. A number of blood-specific lines have provided a means to exploit the exquisite optical clarity that this vertebrate system offers and provide a level of insight into dynamic inflammatory processes previously unavailable. Results We used regulatory regions of the zebrafish lysozyme C (lysC) gene to drive enhanced green fluorescent protein (EGFP) and DsRED2 expression in a manner that completely recapitulated the endogenous expression profile of lysC. Labeled cells were shown by co-expression studies and FACS analysis to represent a subset of macrophages and likely also granulocytes. Functional assays within transgenic larvae proved that these marked cells possess hallmark traits of myelomonocytic cells, including the ability to migrate to inflammatory sources and phagocytose bacteria. Conclusion These reporter lines will have utility in dissecting the genetic determinants of commitment to the myeloid lineage and in further defining how lysozyme-expressing cells participate during inflammation.
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            Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-gamma and PTEN.

             Li Pu,  Bing Song,  Teiji Wada (2006)
            Wound healing is essential for maintaining the integrity of multicellular organisms. In every species studied, disruption of an epithelial layer instantaneously generates endogenous electric fields, which have been proposed to be important in wound healing. The identity of signalling pathways that guide both cell migration to electric cues and electric-field-induced wound healing have not been elucidated at a genetic level. Here we show that electric fields, of a strength equal to those detected endogenously, direct cell migration during wound healing as a prime directional cue. Manipulation of endogenous wound electric fields affects wound healing in vivo. Electric stimulation triggers activation of Src and inositol-phospholipid signalling, which polarizes in the direction of cell migration. Notably, genetic disruption of phosphatidylinositol-3-OH kinase-gamma (PI(3)Kgamma) decreases electric-field-induced signalling and abolishes directed movements of healing epithelium in response to electric signals. Deletion of the tumour suppressor phosphatase and tensin homolog (PTEN) enhances signalling and electrotactic responses. These data identify genes essential for electrical-signal-induced wound healing and show that PI(3)Kgamma and PTEN control electrotaxis.
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              Reversible oxidation and inactivation of the tumor suppressor PTEN in cells stimulated with peptide growth factors.

              Stimulation of cells with various peptide growth factors induces the production of phosphatidylinositol 3,4,5-trisphosphate (PIP3) through activation of phosphatidylinositol 3-kinase. The action of this enzyme is reversed by that of the tumor suppressor PTEN. With the use of cells overexpressing NADPH oxidase 1 or peroxiredoxin II, we have now shown that H2O2 produced in response to stimulation of cells with epidermal growth factor or platelet-derived growth factor potentiates PIP3 generation and activation of the protein kinase Akt induced by these growth factors. We also show that a small fraction of PTEN molecules is transiently inactivated as a result of oxidation of the essential cysteine residue of this phosphatase in various cell types stimulated with epidermal growth factor, platelet-derived growth factor, or insulin. These results suggest that the activation of phosphatidylinositol 3-kinase by growth factors might not be sufficient to induce the accumulation of PIP3 because of the opposing activity of PTEN and that the concomitant local inactivation of PTEN by H2O2 might be needed to increase the concentration of PIP3 sufficiently to trigger downstream signaling events. Furthermore, together with previous observations, our data indicate that peroxiredoxin likely participates in PIP3 signaling by modulating the local concentration of H2O2.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                0028-0836
                1476-4687
                27 April 2009
                3 June 2009
                18 June 2009
                7 January 2010
                : 459
                : 7249
                : 996-999
                Affiliations
                [1 ]Departement of Systems Biology, Harvard Medical School, Boston MA 02115, USA
                [2 ]Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
                [4 ]Division of Hematology/Oncology, Department of Pediatrics, Children's Hospital, Harvard Medical School, Boston, MA 02114, USA
                Author notes
                [3]

                Current address: Karlsruhe Institute of Technology, Forschungszentrum Karlsruhe GmbH, 76344 Eggenstein-Leopoldshafen, Germany

                [*]

                These authors contributed equally to this work

                Author Information Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. Correspondence and requests for materials should be addressed to P.N. ( Philipp_Niethammer@ 123456hms.harvard.edu ).
                Article
                nihpa112908
                10.1038/nature08119
                2803098
                19494811
                Funding
                Funded by: National Institute of General Medical Sciences : NIGMS
                Award ID: R01 GM023928-30 ||GM
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