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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Vydáno v:	Journal of allergy and clinical immunology Ročník 144; číslo 1; s. 267 - 279.e4
Hlavní autoři:	Impellizzieri, Daniela, Ridder, Frederike, Raeber, Miro E., Egholm, Cecilie, Woytschak, Janine, Kolios, Antonios G.A., Legler, Daniel F., Boyman, Onur
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Elsevier Inc 01.07.2019 Elsevier Limited
Témata:	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
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Shrnutí:	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]
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0091-6749 1097-6825 1097-6825
DOI:	10.1016/j.jaci.2019.01.042