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Exploring the HIFs, buts and maybes of hypoxia signalling in disease: lessons from zebrafish models.

Elks PM, Renshaw SA, Meijer AH, Walmsley SR, van Eeden FJ - Dis Model Mech (2015)

Bottom Line: These findings highlight the need for new whole-organism models of disease to elucidate these complex regulatory mechanisms.Findings from such models identify HIF as an integral player in the disease processes.They also highlight HIF pathway components and their targets as potential therapeutic targets against conditions that range from cancers to infectious disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Infection and Immunity, Medical School, The University of Sheffield, Sheffield, S10 2RX, UK The Bateson Centre, The University of Sheffield, Sheffield, S10 2TN, UK p.elks@sheffield.ac.uk.

No MeSH data available.


Related in: MedlinePlus

Hif-1α stabilisation reduces bacterial burden in zebrafish embryos. (A) Zebrafish embryos were infected with Mycobacterium marinum (red) at 1 day postfertilisation by injection into the caudal vein. By 4 days postinfection, foci of M. marinum (red) are surrounded by infected and uninfected leukocytes (green; L-plastin antibody staining) in structures known as granulomas. (B) Stabilisation of Hif-1α, using dominant active (DA) Hif-1αb reduces the bacterial burden of zebrafish embryos compared with phenol red (PR)-injected controls. However, when macrophage numbers are depleted using an antisense oligonucleotide morpholino to the crucial macrophage transcription factor irf-8 (Li et al., 2011), bacteria are able to proliferate in an uncontrolled manner and dominant active Hif-1αb stabilisation is powerless to decrease infection. Neutrophils, marked in green (using the Tg(mpx:GFP)i114 transgenic zebrafish line; Renshaw et al., 2006), have emerging roles in granuloma formation and maintenance, but without macrophages present they cannot control infection alone. Images are from P.M.E. and A.H.M., unpublished observations.
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DMM021865F4: Hif-1α stabilisation reduces bacterial burden in zebrafish embryos. (A) Zebrafish embryos were infected with Mycobacterium marinum (red) at 1 day postfertilisation by injection into the caudal vein. By 4 days postinfection, foci of M. marinum (red) are surrounded by infected and uninfected leukocytes (green; L-plastin antibody staining) in structures known as granulomas. (B) Stabilisation of Hif-1α, using dominant active (DA) Hif-1αb reduces the bacterial burden of zebrafish embryos compared with phenol red (PR)-injected controls. However, when macrophage numbers are depleted using an antisense oligonucleotide morpholino to the crucial macrophage transcription factor irf-8 (Li et al., 2011), bacteria are able to proliferate in an uncontrolled manner and dominant active Hif-1αb stabilisation is powerless to decrease infection. Neutrophils, marked in green (using the Tg(mpx:GFP)i114 transgenic zebrafish line; Renshaw et al., 2006), have emerging roles in granuloma formation and maintenance, but without macrophages present they cannot control infection alone. Images are from P.M.E. and A.H.M., unpublished observations.

Mentions: Concurrent studies in zebrafish larvae shown that Hif-α signalling is important in in vivo infection, and is upregulated in leukocytes when zebrafish are challenged with lipopolysaccharide (a bacterial wall product) in hypoxia or with M. marinum in normoxia (Fig. 4; Elks et al., 2013; Liu et al., 2013). Mycobacterium marinum infection of zebrafish larvae is a well-established vertebrate tuberculosis model that has informed our understanding of the human disease (Berg and Ramakrishnan, 2012; Meijer and van der Vaart, 2014; Stoop et al., 2011). The temporal and spatial resolution of the live zebrafish M. marinum model has been used to demonstrate that Hif-α stabilisation in M. marinum-infected zebrafish macrophages is transient and rapidly downregulated, creating permissive conditions for bacterial growth (Elks et al., 2013). The modulation of Hif-α in zebrafish has demonstrated that this pathway intricately controls the production of neutrophil nitric oxide (NO). Overexpression of Hif-1α stimulated inducible nitric oxide synthase (Nos2a) to produce NO, an important antimicrobial mechanism of leukocytes during infection (Elks et al., 2013, 2014; see Box 1). Interestingly, Hif-1α and Hif-2α were found to have opposing functions on NO production. The stabilisation of Hif-1α primes neutrophils with increased NO levels, allowing the host to deal with infection better. Conversely, decreasing Hif-2α increases neutrophil NO levels (Elks et al., 2013). This complex regulatory signature of different Hif-α variants demonstrates the need for intact in vivo models, such as the zebrafish, with immune cells in their natural tissue environment in order to gain a proper understanding of the mechanisms involved and their precise effect on infection.Fig. 4.


Exploring the HIFs, buts and maybes of hypoxia signalling in disease: lessons from zebrafish models.

Elks PM, Renshaw SA, Meijer AH, Walmsley SR, van Eeden FJ - Dis Model Mech (2015)

Hif-1α stabilisation reduces bacterial burden in zebrafish embryos. (A) Zebrafish embryos were infected with Mycobacterium marinum (red) at 1 day postfertilisation by injection into the caudal vein. By 4 days postinfection, foci of M. marinum (red) are surrounded by infected and uninfected leukocytes (green; L-plastin antibody staining) in structures known as granulomas. (B) Stabilisation of Hif-1α, using dominant active (DA) Hif-1αb reduces the bacterial burden of zebrafish embryos compared with phenol red (PR)-injected controls. However, when macrophage numbers are depleted using an antisense oligonucleotide morpholino to the crucial macrophage transcription factor irf-8 (Li et al., 2011), bacteria are able to proliferate in an uncontrolled manner and dominant active Hif-1αb stabilisation is powerless to decrease infection. Neutrophils, marked in green (using the Tg(mpx:GFP)i114 transgenic zebrafish line; Renshaw et al., 2006), have emerging roles in granuloma formation and maintenance, but without macrophages present they cannot control infection alone. Images are from P.M.E. and A.H.M., unpublished observations.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4631790&req=5

DMM021865F4: Hif-1α stabilisation reduces bacterial burden in zebrafish embryos. (A) Zebrafish embryos were infected with Mycobacterium marinum (red) at 1 day postfertilisation by injection into the caudal vein. By 4 days postinfection, foci of M. marinum (red) are surrounded by infected and uninfected leukocytes (green; L-plastin antibody staining) in structures known as granulomas. (B) Stabilisation of Hif-1α, using dominant active (DA) Hif-1αb reduces the bacterial burden of zebrafish embryos compared with phenol red (PR)-injected controls. However, when macrophage numbers are depleted using an antisense oligonucleotide morpholino to the crucial macrophage transcription factor irf-8 (Li et al., 2011), bacteria are able to proliferate in an uncontrolled manner and dominant active Hif-1αb stabilisation is powerless to decrease infection. Neutrophils, marked in green (using the Tg(mpx:GFP)i114 transgenic zebrafish line; Renshaw et al., 2006), have emerging roles in granuloma formation and maintenance, but without macrophages present they cannot control infection alone. Images are from P.M.E. and A.H.M., unpublished observations.
Mentions: Concurrent studies in zebrafish larvae shown that Hif-α signalling is important in in vivo infection, and is upregulated in leukocytes when zebrafish are challenged with lipopolysaccharide (a bacterial wall product) in hypoxia or with M. marinum in normoxia (Fig. 4; Elks et al., 2013; Liu et al., 2013). Mycobacterium marinum infection of zebrafish larvae is a well-established vertebrate tuberculosis model that has informed our understanding of the human disease (Berg and Ramakrishnan, 2012; Meijer and van der Vaart, 2014; Stoop et al., 2011). The temporal and spatial resolution of the live zebrafish M. marinum model has been used to demonstrate that Hif-α stabilisation in M. marinum-infected zebrafish macrophages is transient and rapidly downregulated, creating permissive conditions for bacterial growth (Elks et al., 2013). The modulation of Hif-α in zebrafish has demonstrated that this pathway intricately controls the production of neutrophil nitric oxide (NO). Overexpression of Hif-1α stimulated inducible nitric oxide synthase (Nos2a) to produce NO, an important antimicrobial mechanism of leukocytes during infection (Elks et al., 2013, 2014; see Box 1). Interestingly, Hif-1α and Hif-2α were found to have opposing functions on NO production. The stabilisation of Hif-1α primes neutrophils with increased NO levels, allowing the host to deal with infection better. Conversely, decreasing Hif-2α increases neutrophil NO levels (Elks et al., 2013). This complex regulatory signature of different Hif-α variants demonstrates the need for intact in vivo models, such as the zebrafish, with immune cells in their natural tissue environment in order to gain a proper understanding of the mechanisms involved and their precise effect on infection.Fig. 4.

Bottom Line: These findings highlight the need for new whole-organism models of disease to elucidate these complex regulatory mechanisms.Findings from such models identify HIF as an integral player in the disease processes.They also highlight HIF pathway components and their targets as potential therapeutic targets against conditions that range from cancers to infectious disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Infection and Immunity, Medical School, The University of Sheffield, Sheffield, S10 2RX, UK The Bateson Centre, The University of Sheffield, Sheffield, S10 2TN, UK p.elks@sheffield.ac.uk.

No MeSH data available.


Related in: MedlinePlus