IL-4 receptor engagement in human neutrophils impairs their migration and extracellular trap formation

Impellizzieri, Daniela; Ridder, Frederike; Raeber, Miro E.; Egholm, Cecilie; Woytschak, Janine; Kolios, Antonios; Legler, Daniel F.; Boyman, Onur

doi:10.1016/j.jaci.2019.01.042

Cited by 66 publications

(113 citation statements)

References 53 publications

(71 reference statements)

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“…Evidence has evolved in support of actions for g c family cytokines on neutrophils, macrophages, and other myeloid cells. For example, IL-4 antagonizes neutrophil expansion and activation (Impellizzieri et al, 2019;Woytschak et al, 2016) whereas IL-2 activates neutrophils to promote killing of Candida (Djeu et al, 1993).…”

Section: Nonclassical Views Of G C Cytokinesmentioning

confidence: 99%

The γc Family of Cytokines: Basic Biology to Therapeutic Ramifications

2019

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The common cytokine receptor g chain, g c , is a component of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21. Mutation of the gene encoding g c results in X-linked severe combined immunodeficiency in humans, and g c family cytokines collectively regulate development, proliferation, survival, and differentiation of immune cells. Here, we review the basic biology of these cytokines, highlighting mechanisms of signaling and gene regulation that have provided insights for immunodeficiency, autoimmunity, allergic diseases, and cancer. Moreover, we discuss how studies of this family stimulated the development of JAK3 inhibitors and present an overview of current strategies targeting these pathways in the clinic, including novel antibodies, antagonists, and partial agonists. The diverse roles of these cytokines on a range of immune cells have important therapeutic implications.

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Section: Nonclassical Views Of G C Cytokinesmentioning

confidence: 99%

The γc Family of Cytokines: Basic Biology to Therapeutic Ramifications

2019

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“…168,169 Rare, however significant side effects 170 and the not yet completely understood effects of IL-4 on innate immune function warrant further investigation. 171,172 Studies investigating the role of TSLP and IL-25 in the context of food allergy are limited, and recent data on the topic are still derived from rodent in vivo and in vitro models. 15,85 Currently, there are trials of biologics targeting TSLP in asthma (NCT02698501), and in combination with cat immunotherapy (NCT02237196), but not food allergies.…”

Section: Antig En -Uns Pecific and Additive A Pproache Smentioning

confidence: 99%

Recent developments and highlights in food allergy

Eiwegger

Hung

Diego

et al. 2019

Allergy

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The achievement of long-lasting, safe treatments for food allergy is dependent on the understanding of the immunological basis of food allergy. Accurate diagnosis is essential for management. In recent years, data from oral food challenges have revealed that routine allergy testing is poor at predicting clinical allergy for tree nuts, almonds in particular. More advanced antigen-based tests including component-resolved diagnostics and epitope reactivity may lead to more accurate diagnosis and selection of therapeutic intervention. Additional diagnostic accuracy may come from cellular tests such as the basophil activation test or mast cell approaches. In the context of clinical trials, cellular tests have revealed specific T-cell and B-cell populations that are more abundant in food-allergic individuals with distinct mechanistic features.Awareness of clinical markers, such as the ability to eat baked forms of milk and egg, continues to inform the understanding of natural tolerance development.Mouse models have allowed for investigation into multiple mechanisms of food allergy including modification of epithelial metabolism, and the induction of regulatory cell subsets and the microbiome. Increasing numbers of children who underwent food immunotherapy enlarged the body of evidence on mechanisms and predictors of treatment success. Experimental immunological markers in conjunction with clinical determinants such as lower age and lower initial specific IgE appear to be of benefit.More research on the optimal dose, preparation, and route of application integrating a high-level safety and efficacy is demanded. Alternatively, biologics blocking TSLP, IL-33, IL-4 and IL-13, or IgE may help to achieve that. K E Y W O R D Sallergy treatment, biologics, food allergy, immune tolerance, immunotherapy | 2357 EIWEGGER Et al.

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“…In a number of different mouse models including sterile inflammation, bacterial infection, helminth infestation, and rheumatoid arthritis, IL-4R signaling was shown to have an inhibitory effect on neutrophils [9][10][11][12]. Human neutrophils isolated from allergic patients, a condition dominated by the presence of IL-4 and IL-13, were less capable of migrating and producing NETs than neutrophils from healthy donors [13]. Thus, we hypothesize that inhibition of neutrophil effector functions in type 2 immune responses constitutes a crucial effect of the IL-4/IL-13-IL-4R system.…”

Section: Introductionmentioning

confidence: 99%

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

2020

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The cytokines interleukin (IL)-4 and IL-13, signaling via the IL-4 receptor (IL-4R), orchestrate type 2 immunity to helminth infections and toxins. Activation of epithelial and myeloid cells, and a transient neutrophils influx initiates type 2 immune responses, which are dominated by basophils, eosinophils, mast cells, B cell immunoglobulin E production, and type 2 T helper and T follicular helper cells. Interestingly, IL-4 and IL-13 can curtail chemotaxis and several effector functions of neutrophils in mice and humans. This inhibitory role of IL-4 and IL-13 probably developed to limit tissue damage by neutrophils during type 2 immunity where a "weep and sweep" response aims at expulsion and decreased fecundity, instead of killing, of macroparasites. Here, we review when IL-4R signaling cytokines appeared during evolution relative to neutrophils and adaptive immunity. Neutrophil-like granular phagocytes were present in invertebrates throughout the bilaterian clade, but we were unable to find data on IL-4, IL-13, or their receptors in invertebrates. Conversely, vertebrates had both adaptive immunity and IL-4, IL-13, and IL-4Rs, suggesting that type 2 cytokines evolved together with adaptive immunity. Further studies are necessary to determine whether IL-4R signaling in neutrophils was established simultaneously with the appearance of adaptive immunity or later.

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IL-4 receptor engagement in human neutrophils impairs their migration and extracellular trap formation

Cited by 66 publications

References 53 publications

The γc Family of Cytokines: Basic Biology to Therapeutic Ramifications

The γc Family of Cytokines: Basic Biology to Therapeutic Ramifications

Recent developments and highlights in food allergy

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

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