Hypoxia-inducible factor–dependent induction of netrin-1 dampens inflammation caused by hypoxia

Rosenberger, Peter; Schwab, Jan M.; Mirakaj, Valbona; Masekowsky, Eva; Mager, Alice; Morote-García, Julio C.; Unertl, K.; Eltzschig, Holger K.

doi:10.1038/ni.1683

Cited by 370 publications

(458 citation statements)

References 48 publications

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“…This finding was corroborated by the lack of RGM-A expression by two well-established endothelial cell lines, human dermal microvascular endothelial cell 1 (HMEC-1) and human umbilical vein endothelial cell (HUVEC) (Fig. 2D) (8).…”

Section: Rgm-a Is Expressed Outside the Cnssupporting

confidence: 49%

“…Appropriate adjusted leukocyte migration and recruitment to the inflammatory site is essential to control inflammation for effective host defense and also to avoid tissue damage due to an aberrant, exacerbated inflammatory response (3,4). To test whether RGM-A is a chemorepulsive cue for PMN migration in vitro, we applied formyl-methionyl-leucyl-phenylalanine (fMLP)-induced chemotaxis using a paracellular flux assay (8). On stimulation by fMLP, granulocytes migrate across a semipermeable membrane seeded with epithelial CaCo cells, forming a cell monolayer (Fig.…”

Section: Rgm-a Reduces Pmn Migration Through the Neogenin Receptor Inmentioning

confidence: 99%

“…Excessive immune cell migration into an inflammatory site might result in tissue destruction and organ dysfunction (functio laesa). Recently, neuronal guidance cues were identified that control and attenuate inappropriate migration and infiltration of leukocytes into acutely inflamed areas (6)(7)(8)(9)(10)(11)(12). Given that the neuronal repellent RGM-A is expressed at inflammatory sites but shares no sequence homology with any other known guidance cues, we explored whether it inhibits leukocyte migration in vitro and in vivo (7,12,13).…”

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confidence: 99%

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Repulsive guidance molecule-A (RGM-A) inhibits leukocyte migration and mitigates inflammation

Mirakaj

Brown

Laucher

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Rgm-a Is Expressed Outside the Cnssupporting

confidence: 49%

Section: Rgm-a Reduces Pmn Migration Through the Neogenin Receptor Inmentioning

confidence: 99%

mentioning

confidence: 99%

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Repulsive guidance molecule-A (RGM-A) inhibits leukocyte migration and mitigates inflammation

Mirakaj

Brown

Laucher

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…For example, the anti-inflammatory protein netrin-1 was shown to be regulated by both NF!B [42] and HIF [43]. We speculate that this duality in the transcriptional crosstalk for regulating both pro-and anti-inflammatory genes might be dependent on other factors in order to resolve inflammation.…”

Section: Discussionmentioning

confidence: 92%

NFκB and HIF display synergistic behaviour during hypoxic inflammation

Brüning

Fitzpatrick

Frank

et al. 2011

Cell. Mol. Life Sci.

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The oxygen-sensitive transcription factor Hypoxia Inducible Factor (HIF) is a key regulator of gene expression during adaptation to hypoxia. Crucially, inflamed tissue often displays regions of prominent hypoxia. Recent studies have shown HIF signalling is intricately linked to that of the pro-inflammatory transcription factor Nuclear factor kappa B (NF!B) during hypoxic inflammation. Here we describe the relative temporal contributions of each to hypoxia-induced inflammatory gene expression and investigate the level of crosstalk between the two pathways using a novel Gaussia princeps luciferase (Gluc) reporter system. Under the control of an active promoter, Gluc is expressed and secreted into the cell culture media, where it can be sampled and measured over time. Thus Gluc constructs under the control of either HIF or NF!B were used to resolve their temporal transcriptional dynamics in response to hypoxia and to cytokine stimuli respectively. We also investigated the interactions between HIF and NF!B activities using a construct containing the sequence from the promoter of the inflammatory gene cyclooxygenase 2 (COX-2), which includes functionally active binding sites for both HIF and NF!B. Finally, based on our experimental data, we constructed a mathematical model of the binding affinities of HIF and NF!B to their respective response elements to analyse transcriptional crosstalk. Taken together, these data reveal distinct temporal HIF and NF!B transcriptional activities in response to hypoxic inflammation. Furthermore, we demonstrate synergistic activity between these two transcription factors on the regulation of the COX-2 promoter, implicating a coordinated role for both HIF and NF!B in the expression of COX-2 in hypoxic inflammation.

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“…With identification of the newer roles for netrin-1 other than its involvement in nervous system development, research is currently focused on understanding the mechanism of netrin-1 induction. More recent studies have reported the critical role of hypoxia inducible factor-1a (Hif-1a) in regulating endogenous netrin-1 expression [23]. Transcription factor Hif-1a is translocated into the cell nuclei in response to tissue hypoxia where it regulates expression of a plethora of genes that help cellular and tissue responses to low oxygen presence to maintain oxygen homeostasis in the biological system [24][25][26].…”

Section: Netrin-1 Gene Delivery To the Heartmentioning

confidence: 99%

Cytoprotective and Proangiogenic Activity of Ex-Vivo Netrin-1 Transgene Overexpression Protects the Heart Against Ischemia/Reperfusion Injury

Durrani

Haider

Ahmed

et al. 2012

Stem Cells and Development

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In continuation of a previous work that transgene expression of sonic hedgehog promoted neo-vascularization via netrin-1 release, the current study was aimed at assessing the anti-apoptotic and pro-angiogenic role of netrin-1 transgene overexpression in the ischemic myocardium. pLP-Adeno-X ViralTrak vectors containing netrin-1 cDNA amplified from rat mesenchymal stem cells (Ad-netrin) or without a therapeutic gene (Ad-null) were constructed and transfected into HEK-293 cells to produce Ad-netrin and Ad-null vectors. Sca-1 + -like cells were isolated and propagated in vitro and were successfully transduced with Ad-netrin transduced Sca-1 + cells ( Net Sca-1 + ) and Ad-null transduced Sca-1 + cells ( Null Sca-1 + ). Overexpression of netrin-1 in Net Sca-1 + was confirmed by reverse transcription-polymerase chain reaction and western blot. Neonatal cardiomyocytes and rat endothelial cells expressed netrin-1 specific receptor Uncoordinated-5b and the conditioned medium from Net Sca-1 + cells was protective for both the cell types against oxidant stress. For in vivo studies, the rat model of myocardial ischemia/reperfusion injury was developed in female Wistar rats by left anterior descending coronary artery occlusion for 45 min followed by reperfusion. The animals were grouped to receive 70 mL of Dulbecco's modified Eagle's medium without cells (group-1), containing 2 · 10 6 Null Sca-1 + cells (group-2) and Net Sca-1 + cells (group-3). Net Sca-1 + cells significantly reduced ischemia/reperfusion injury in the heart and preserved the global heart function in group-3 (P < 0.05 vs. groups-1 and group-2). Ex-vivo netrin-1 overexpression in the heart increased NOS activity in the heart. Blood vessel density was significantly higher in group-3 (P < 0.05 vs. controls). We concluded that netrin-1 decreased apoptosis in cardiomyocytes and endothelial cells via activation of Akt. Netrin-1 transgene expression was proangiogenic and effectively reduced ischemia/reperfusion injury to preserve global heart function.

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Hypoxia-inducible factor–dependent induction of netrin-1 dampens inflammation caused by hypoxia

Cited by 370 publications

References 48 publications

Repulsive guidance molecule-A (RGM-A) inhibits leukocyte migration and mitigates inflammation

Repulsive guidance molecule-A (RGM-A) inhibits leukocyte migration and mitigates inflammation

NFκB and HIF display synergistic behaviour during hypoxic inflammation

Cytoprotective and Proangiogenic Activity of Ex-Vivo Netrin-1 Transgene Overexpression Protects the Heart Against Ischemia/Reperfusion Injury

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