Tissue-specific molecular immune response to lipopolysaccharide challenge in emaciated anadromous Arctic charr

Philip, Anju M.; Jørgensen, Even H.; Maule, Alec G.; Vijayan, Mathilakath M.

doi:10.1016/j.dci.2014.02.012

Cited by 15 publications

(11 citation statements)

References 43 publications

(70 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cytokine levels are known to be temporally regulated in response to infection, and we might have missed the peak levels in proinflammatory cytokine expression typically observed in the first few hours following immune insult (40). Moreover, the significantly high expression of the antiinflammatory cytokine IL-10 suggests altered expression and distribution of cellular junction proteins (18,33).…”

Section: Discussionmentioning

confidence: 99%

Development of a Zebrafish Sepsis Model for High-Throughput Drug Discovery

Philip

Wang

Mauro

et al. 2017

Mol Med

Self Cite

View full text Add to dashboard Cite

Sepsis is a leading cause of death worldwide. Current treatment modalities remain largely supportive. Intervention strategies focused on inhibiting specific mediators of the inflammatory host response have been largely unsuccessful, a consequence of an inadequate understanding of the complexity and heterogeneity of the innate immune response. Moreover, the conventional drug-development pipeline is time-consuming and expensive, and the low success rates associated with cell-based screens underline the need for whole-organism screening strategies, especially for complex pathological processes. Here, we established a lipopolysaccharide (LPS)-induced zebrafish endotoxemia model, which exhibits the major hallmarks of human sepsis, including edema and tissue/organ damage, increased vascular permeability and vascular leakage accompanied by altered expression of cellular junction proteins, increased cytokine expression, immune cell activation and reactive oxygen species (ROS) production, reduced circulation and increased platelet aggregation. We tested the suitability of the model for phenotype-based drug screening using three primary readouts: mortality, vascular leakage and ROS production. Preliminary screening identified fasudil, a drug known to protect against vascular leakage in murine models, as a lead hit, thereby validating the utility of our model for sepsis drug screens. This zebrafish sepsis model has the potential to rapidly analyze sepsis-associated pathologies and cellular processes in the whole organism, as well as to screen and validate many compounds that can modify sepsis pathology in vivo.

show abstract

Section: Discussionmentioning

confidence: 99%

Development of a Zebrafish Sepsis Model for High-Throughput Drug Discovery

Philip

Wang

Mauro

et al. 2017

Mol Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…We recently showed that suppressors of cytokine signaling (SOCS) transcript levels in the liver are modulated by stress and/or cortisol treatment in rainbow trout [14, 19]. The SOCS genes act as negative regulators of both cytokine and GH signaling in mammals by targeting the JAK/STAT pathway [20].…”

Section: Introductionmentioning

confidence: 99%

“…Many of the SOCS members also have multiple copies, including three trout SOCS-2s and two SOCS-3s, likely a consequence of fish-specific whole genome duplication events and gene duplication or lineage-specific genome duplication [23]. Although the functional significance of SOCS transcript abundance is unclear in fish, the mRNA abundance of SOCS1-3 have been shown to be modulated by cytokines, immunostimulants, nutritional status and cortisol exposure in fish [14, 19, 22, 23]. Consequently, SOCS upregulation may limit GH, cytokine and LPS signaling, given they all share the JAK/STAT signaling pathway [16, 20].…”

Section: Introductionmentioning

confidence: 99%

“…The liver was specifically used in this study because it is a key metabolic tissue that is essential for energy substrate repartitioning during stress, and is also a key target for cortisol action via glucocorticoid receptor (GR) signaling [1, 24, 25]. Also, recent studies clearly implicate liver as an immune-responsive tissue in fish [14, 19, 26], in addition to being a key organ for growth involving IGF production in response to GH stimulations in fish [10]. Our results indicate that cortisol upregulation of SOCS-1 and SOCS-2 may be a key mechanism reducing GH signaling and suppressing cytokine production during stress in fish.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Stress-Immune-Growth Interactions: Cortisol Modulates Suppressors of Cytokine Signaling and JAK/STAT Pathway in Rainbow Trout Liver

Philip

Vijayan

2015

PLoS ONE

Self Cite

View full text Add to dashboard Cite

Chronic stress is a major factor in the poor growth and immune performance of salmonids in aquaculture. However, the molecular mechanisms linking stress effects to growth and immune dysfunction is poorly understood. The suppressors of cytokine signaling (SOCS), a family of genes involved in the inhibition of JAK/STAT pathway, negatively regulates growth hormone and cytokine signaling, but their role in fish is unclear. Here we tested the hypothesis that cortisol modulation of SOCS gene expression is a key molecular mechanism leading to growth and immune suppression in response to stress in fish. Exposure of rainbow trout (Oncorhynchus mykiss) liver slices to cortisol, mimicking stress level, upregulated SOCS-1 and SOCS-2 mRNA abundance and this response was abolished by the glucocorticoid receptor antagonist mifepristone. Bioinformatics analysis confirmed the presence of putative glucocorticoid response elements in rainbow trout SOCS-1 and SOCS-2 promoters. Prior cortisol treatment suppressed acute growth hormone (GH)-stimulated IGF-1 mRNA abundance in trout liver and this involved a reduction in STAT5 phosphorylation and lower total JAK2 protein expression. Prior cortisol treatment also suppressed lipopolysaccharide (LPS)-induced IL-6 but not IL-8 transcript levels; the former but not the latter cytokine expression is via JAK/STAT phosphorylation. LPS treatment reduced GH signaling, but this was associated with the downregulation of GH receptors and not due to the upregulation of SOCS transcript levels by this endotoxin. Collectively, our results suggest that upregulation of SOCS-1 and SOCS-2 transcript levels by cortisol, and the associated reduction in JAK/STAT signaling pathway, may be a novel mechanism leading to growth reduction and immune suppression during stress in trout.

show abstract

“…Salvelinus alpinus [22], Oncorhynchus mykiss [23][24][25] and Ictalurus punctatus [26]. In some of these 81 reports, the expression of SOCS genes in response to pathogen-associated molecular patterns (PAMPs), 82 such as lipopolysaccharides (LPS) and poly I:C, has been examined [15,17,25].…”

mentioning

confidence: 99%