Evolution and function of interleukin-4 receptor signaling in adaptive immunity and neutrophils

Heeb, Lukas E. M.; Egholm, Cecilie; Boyman, Onur

doi:10.1038/s41435-020-0095-7

Cited by 59 publications

(61 citation statements)

References 56 publications

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“…Effects on mpx transcript were not observed in the il4/13b −/− mutant, suggesting a divergent function for these paralogs in neutrophils in zebrafish. In mammals, neutrophils express IL-4 type I receptor ( 61 , 62 ), and recent evidence suggests that IL-4– and IL-13–mediated signaling in both mouse and human neutrophils inhibits their migration and effector functions ( 63 , 64 ) to reduce inflammation and tissue damage during type 2 responses ( 65 ). To date, there is no definitive evidence for a role for fish IL-4/13 paralogs in controlling neutrophils.…”

Section: Discussionmentioning

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

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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: Discussionmentioning

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

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“…IL‐13 cytokine serum levels were significantly high in atopic and nonatopic asthma patients compared to healthy controls. IL‐4 and IL‐13 can curtail chemotaxis and several effector functions of neutrophils in humans 98,99 . In a recent analysis of the QUEST trial, dupilumab reduced severe exacerbation rates, improved FEV 1 and asthma control, and suppressed T2 inflammatory biomarkers in patients with uncontrolled, moderate‐to‐severe asthma with or without evidence of allergic asthma 97 .…”

Section: Key Recommendations (Biologicals Are Mentioned In Alphabeticmentioning

confidence: 99%

“…asthma encompasses several pathways that are concomitantly activated, including cells of the innate immune system such innate lymphoid cells, macrophages, neutrophils and natural killer T cells which are effective producers of a variety of cytokines and seem to play important roles in the development of nonallergic asthma. 27,30,32 IL-13 cytokine serum levels were significantly high in atopic and nonatopic asthma patients compared to healthy controls.IL-4 and IL-13 can curtail chemotaxis and several effector functions of neutrophils in humans 98,99. In a recent analysis of the QUEST trial, dupilumab reduced severe exacerbation rates, improved FEV 1 and asthma control, and suppressed T2 inflammatory biomarkers in patients with uncontrolled, moderate-to-severe asthma with or without evidence of allergic asthma 97.…”

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confidence: 99%

EAACI Biologicals Guidelines—Recommendations for severe asthma

Agache

Akdiş

et al. 2020

Allergy

203

179

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Severe asthma imposes a significant burden on patients, families and healthcare systems. Management is difficult, due to disease heterogeneity, co-morbidities, complexity in care pathways and differences between national or regional healthcare systems. Better understanding of the mechanisms has enabled a stratified approach to the management of severe asthma, supporting the use of targeted treatments with biologicals. However, there are still many issues that require further clarification. These include selection of a certain biological (as they all target overlapping disease phenotypes), the definition of response, strategies to enhance the responder rate, the duration of treatment and its regimen (in the clinic or home-based) and its costeffectiveness. The EAACI Guidelines on the use of biologicals in severe asthma follow the GRADE approach in formulating recommendations for each biological and each outcome. In addition, a management algorithm for the use of biologicals in the clinic is proposed, together with future approaches and research priorities.

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“…Effects on mpx transcript were not observed in the il4/13b −/− mutant, suggesting a divergent function for these paralogues in neutrophils in zebrafish. In mammals, neutrophils express IL-4 type I receptor (46,47) and recent evidence suggests that IL-4 and IL-13-mediated signaling in both mouse and human neutrophils inhibits their migration and effector functions (48,49), in order to reduce inflammation and tissue damage during type-2 responses (50). To date, there is no definitive evidence for a role for fish il4/13 paralogues in controlling neutrophils.…”

Section: Discussionmentioning

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

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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Evolution and function of interleukin-4 receptor signaling in adaptive immunity and neutrophils

Cited by 59 publications

References 56 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

EAACI Biologicals Guidelines—Recommendations for severe asthma

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

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