Induction of innate cytokine responses by respiratory mucosal challenge with R848 in zebrafish, mice, and humans

Progatzky, Fränze; Jha, Akhilesh; Wane, Madina; Thwaites, Ryan S.; Makris, Spyridon; Shattock, Robin J.; Johansson, Cecilia; Openshaw, Peter; Bugeon, Laurence; Hansel, Trevor T.; Dallman, Margaret J.

doi:10.1016/j.jaci.2019.04.003

Cited by 12 publications

(20 citation statements)

References 16 publications

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“…R848 gill challenge was performed as previously described ( 51 ) using 5 μl of R848 (0.5 mg/ml; InvivoGen) applied to the gills for 5 min. Following completion of the procedure, fish were returned to fresh system water and monitored for their recovery.…”

Section: Methodsmentioning

confidence: 99%

“…We next sought to investigate the importance of IL-4/13a and IL-4/13b in modulating an inflammatory response in the gills to an exogenous source of irritant. To induce gill inflammation, we used an intervention we have recently established, whereby a solution of R848, a synthetic compound that mimics viral ssRNA and interacts with TLR7/8 in mammals (57), is applied directly to the gills (51). Gene expression was analyzed by qPCR at 1 and 8 h to evaluate the kinetics of the response (Fig.…”

Section: Loss Of Il-4/13a and Il-4/13b Leads To An Enhanced Type 1 Rementioning

confidence: 99%

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Zebrafish IL-4–like Cytokines and IL-10 Suppress Inflammation but Only IL-10 Is Essential for Gill Homeostasis

Bottiglione

Dee

Lea

et al. 2020

The Journal of Immunology

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Mucosal surfaces such as fish gills interface between the organism and the external environment and as such are major sites of foreign Ag encounter. In the gills, the balance between inflammatory responses to waterborne pathogens and regulatory responses toward commensal microbes is critical for effective barrier function and overall fish health. In mammals, IL-4 and IL-13 in concert with IL-10 are essential for balancing immune responses to pathogens and suppressing inflammation. Although considerable progress has been made in the field of fish immunology in recent years, whether the fish counterparts of these key mammalian cytokines perform similar roles is still an open question. In this study, we have generated IL-4/13A and IL-4/13B mutant zebrafish (Danio rerio) and, together with an existing IL-10 mutant line, characterized the consequences of loss of function of these cytokines. We demonstrate that IL-4/13A and IL-4/13B are required for the maintenance of a Th2-like phenotype in the gills and the suppression of type 1 immune responses. As in mammals, IL-10 appears to have a more striking anti-inflammatory function than IL-4–like cytokines and is essential for gill homeostasis. Thus, both IL-4/13 and IL-10 paralogs in zebrafish exhibit aspects of conserved function with their mammalian counterparts.

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Section: Methodsmentioning

confidence: 99%

Section: Loss Of Il-4/13a and Il-4/13b Leads To An Enhanced Type 1 Rementioning

confidence: 99%

Zebrafish IL-4–like Cytokines and IL-10 Suppress Inflammation but Only IL-10 Is Essential for Gill Homeostasis

Bottiglione

Dee

Lea

et al. 2020

The Journal of Immunology

Self Cite

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show abstract

“…We next sought to investigate the importance of il4/13a and il4/13b in modulating an inflammatory response in the gills to an exogenous source of irritant. In order to induce gill inflammation, we used an intervention we have recently established, whereby a solution of Resiquimod (R848), a synthetic compound that mimics viral ssRNA and interacts with TLR7/8 in mammals (39), is applied directly to the gills (33). Gene expression was analyzed by qPCR at 1 h and 8 h in order to evaluate the kinetics of the response (Figure 5A).…”

Section: Resultsmentioning

confidence: 99%

“…Recent work has described the use of Resiquimod (R848) in inducing inflammation and cytokine response in zebrafish gills (33), highlighting similarities with mouse and human nasal mucosa. We used Resiquimod to induce inflammation in the gills and found that loss of both il4/13a and il4/13b lead to an enhanced response in the gills of double mutants, which appeared to be type-1-driven, in agreement with transcriptome data in the steady-state.…”

Section: Discussionmentioning

confidence: 99%

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Zebrafish IL-4-like cytokines and IL-10 suppress inflammation but only IL-10 is essential for gill homeostasis

Bottiglione

Dee

Lea

et al. 2020

Preprint

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26Healthy fish stocks are central to global food security. Key to fish health is robust 27 immunity at mucosal surfaces, and especially at the gills. However, a balance must be 28 struck between tolerating commensal microorganisms and reacting appropriately 29 toward pathogens. In mammals, IL-4 and IL-13 in concert with IL-10 are essential 30 for balancing immune response to pathogens and suppressing inflammation. Whether 31 their fish counterparts perform similar roles is an open question. Here, we have 32 generated IL-4/13A and IL-4/13B mutant zebrafish and, together with existing IL-10 33 mutants, characterized the consequences of loss-of-function of these cytokines. We 34 demonstrate that these cytokines are required to suppress inflammation. Further, IL-35 4/13A and IL-4/13B are required for the maintenance of a Th2-like phenotype in the 36 gills. As in mammals, IL-10 appears to have a more striking anti-inflammatory 37 function than IL-4-like cytokines. Thus, both IL-10 and IL-4/13 paralogues in 38 zebrafish exhibit aspects of conserved function with their mammalian counterparts. 39 40 42cytokines that participate in several physiological processes but are mainly known for 43 stimulating type 2 immune responses (1), characterised by mucus overproduction, IgE 44 antibody production, eosinophilia and differentiation of alternatively activated (M2) 45 macrophages (2). These responses confer protection against parasites but, when 46 inappropriately activated, contribute to the development of asthma and allergic 47 inflammation (1). IL-4 and IL-13 are secreted by CD4 + Th2 cells, basophils, 48 eosinophils, mast cells and group 2 innate lymphoid cells (ILC2s) (3). They exert 49 their functions by binding to two types of receptor complexes: a type I receptor, 50 3 constituted by the IL-4Rα chain and the IL-2R common γ chain (γc) and a type II 51 receptor, which comprises IL-4Rα chain and IL-13Rα1 subunits. Both type I and type 52 II receptors signal through STAT6 transcription factor binding to promoter elements 53 within IL-4/IL-13 responsive genes (4). IL-4 and IL-13 suppress inflammatory 54 responses by antagonising production of TNFα, IL-1β and other pro-inflammatory 55 mediators (5) and act in opposition to IFN-γ, the canonical Th1 (type 1) cytokine (6). 56Indeed, co-ordinately with inducing type 2 immune response, IL-4 and IL-13 suppress 57 type 1 responses, characterised by immune cell mediated destruction of cells infected 58 with intracellular pathogens (7). 59Although IL-4 and IL-13 can negatively regulate inflammatory responses, IL-60 10 has the more central anti-inflammatory role in mammals, potently suppressing 61 IFN-γ responses. IL-10 can suppress a range of aberrant immune responses including 62 both type 1 and type 2 responses (8). IL-10 is produced by many cell types (9). It 63 regulates CD4 + Treg cell differentiation and function, and it is important in 64 maintaining homeostasis at mucosal surfaces (10). 65Evidence is emerging that fish immune responses can also be classified as 66 type 1 or t...

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Multi-omics analysis of zebrafish response to tick saliva reveals biological processes associated with alpha-Gal syndrome

Vaz-Rodrigues,

Mazuecos,

Villar

et al. 2023

Biomedicine & Pharmacotherapy

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Induction of innate cytokine responses by respiratory mucosal challenge with R848 in zebrafish, mice, and humans

Cited by 12 publications

References 16 publications

Zebrafish IL-4–like Cytokines and IL-10 Suppress Inflammation but Only IL-10 Is Essential for Gill Homeostasis

Zebrafish IL-4–like Cytokines and IL-10 Suppress Inflammation but Only IL-10 Is Essential for Gill Homeostasis

Zebrafish IL-4-like cytokines and IL-10 suppress inflammation but only IL-10 is essential for gill homeostasis

Multi-omics analysis of zebrafish response to tick saliva reveals biological processes associated with alpha-Gal syndrome

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