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

Type 2 immunity serves to resist parasitic helminths, venoms, and toxins, but the role and regulation of neutrophils during type 2 immune responses are controversial. Helminth models suggested a contribution of neutrophils to type 2 immunity, whereas neutrophils are associated with increased disease...

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Bibliographic Details
Published in:Journal of allergy and clinical immunology Vol. 144; no. 1; pp. 267 - 279.e4
Main Authors: Impellizzieri, Daniela, Ridder, Frederike, Raeber, Miro E., Egholm, Cecilie, Woytschak, Janine, Kolios, Antonios G.A., Legler, Daniel F., Boyman, Onur
Format: Journal Article
Language:English
Published: United States Elsevier Inc 01.07.2019
Elsevier Limited
Subjects:
Allergies
Allergy
Animals
Asthma
Blood & organ donations
Cell Movement - physiology
Chemokine receptors
Chemotaxis
CXCR2 protein
CXCR4 protein
Cytokines
Disease
Extracellular Traps - physiology
Flow cytometry
Human subjects
Humans
Hypotheses
IL-13
IL-4
IL-4 receptor
Immune response
Infections
Inflammation
Inflammatory diseases
innate immunity
Interleukin 13
Interleukin 4
Interleukin-13 - physiology
Interleukin-4 - physiology
Leukocyte migration
Leukocytes (neutrophilic)
Ligands
Mice, Knockout
neutrophil
Neutrophils
Neutrophils - physiology
Peripheral blood
Receptors, Interleukin-4 - genetics
Allergy
AD
PMA
IL-4 receptor
IL-4
IL-13
neutrophil
G-CSF
MPO
IL-4R
STAT
innate immunity
inflammation
pSTAT
HD
NET
ISSN:0091-6749, 1097-6825, 1097-6825
Online Access:Get full text
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Summary:Type 2 immunity serves to resist parasitic helminths, venoms, and toxins, but the role and regulation of neutrophils during type 2 immune responses are controversial. Helminth models suggested a contribution of neutrophils to type 2 immunity, whereas neutrophils are associated with increased disease severity during type 2 inflammatory disorders, such as asthma. We sought to evaluate the effect of the prototypic type 2 cytokines IL-4 and IL-13 on human neutrophils. Human neutrophils from peripheral blood were assessed without or with IL-4 or IL-13 for (1) expression of IL-4 receptor subunits, (2) neutrophil extracellular trap (NET) formation, (3) migration toward CXCL8 in vitro and in humanized mice, and (4) CXCR1, CXCR2, and CXCR4 expression, as well as (5) in nonallergic versus allergic subjects. Human neutrophils expressed both types of IL-4 receptors, and their stimulation through IL-4 or IL-13 diminished their ability to form NETs and migrate toward CXCL8 in vitro. Likewise, in vivo chemotaxis in NOD-scid-Il2rg−/− mice was reduced in IL-4–stimulated human neutrophils compared with control values. These effects were accompanied by downregulation of the CXCL8-binding chemokine receptors CXCR1 and CXCR2 on human neutrophils on IL-4 or IL-13 stimulation in vitro. Ex vivo analysis of neutrophils from allergic patients or exposure of neutrophils from nonallergic subjects to allergic donor serum in vitro impaired their NET formation and migration toward CXCL8, thereby mirroring IL-4/IL-13–stimulated neutrophils. IL-4 receptor signaling in human neutrophils affects several neutrophil effector functions, which bears important implications for immunity in type 2 inflammatory disorders. [Display omitted]
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ISSN:0091-6749
1097-6825
1097-6825
DOI:10.1016/j.jaci.2019.01.042