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Interleukin-4 receptor engagement in human neutrophils impairs their migration and extracellular trap formation.
Journal of Allergy and Clinical Immunology 2019 Februrary 13
BACKGROUND: Type 2 immunity serves to resist parasitic helminths, venoms and toxins, but the role and regulation of neutrophils during type 2 immune responses is 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.
OBJECTIVE: To evaluate the impact of the prototypic type 2 cytokines interleukin-4 (IL-4) and IL-13 on human neutrophils.
METHODS: Human neutrophils from peripheral blood were assessed without or with IL-4 or IL-13 for (i) expression of IL-4 receptor (IL-4R) subunits; (ii) neutrophil extracellular trap (NET) formation; (iii) migration toward CXC chemokine ligand 8 (CXCL8) in vitro and in humanized mice; (iv) CXC chemokine receptor 1 (CXCR1), CXCR2, and CXCR4 expression; and (v) in non-allergic versus allergic subjects.
RESULTS: Human neutrophils expressed both types of IL-4Rs and their stimulation via 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 to controls. These effects were accompanied by downregulation of CXCL8-binding chemokine receptors CXCR1 and CXCR2 on human neutrophils upon IL-4 or IL-13 stimulation in vitro. Ex vivo analysis of neutrophils from allergic patients or exposure of neutrophils from non-allergic individuals to allergic donors' serum in vitro impaired their NET formation and migration toward CXCL8, thereby mirroring IL-4/IL-13-stimulated neutrophils.
CONCLUSION: Signaling in human neutrophils affects several neutrophil effector functions, which bears important implications for immunity in type 2 inflammatory disorders.
OBJECTIVE: To evaluate the impact of the prototypic type 2 cytokines interleukin-4 (IL-4) and IL-13 on human neutrophils.
METHODS: Human neutrophils from peripheral blood were assessed without or with IL-4 or IL-13 for (i) expression of IL-4 receptor (IL-4R) subunits; (ii) neutrophil extracellular trap (NET) formation; (iii) migration toward CXC chemokine ligand 8 (CXCL8) in vitro and in humanized mice; (iv) CXC chemokine receptor 1 (CXCR1), CXCR2, and CXCR4 expression; and (v) in non-allergic versus allergic subjects.
RESULTS: Human neutrophils expressed both types of IL-4Rs and their stimulation via 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 to controls. These effects were accompanied by downregulation of CXCL8-binding chemokine receptors CXCR1 and CXCR2 on human neutrophils upon IL-4 or IL-13 stimulation in vitro. Ex vivo analysis of neutrophils from allergic patients or exposure of neutrophils from non-allergic individuals to allergic donors' serum in vitro impaired their NET formation and migration toward CXCL8, thereby mirroring IL-4/IL-13-stimulated neutrophils.
CONCLUSION: Signaling in human neutrophils affects several neutrophil effector functions, which bears important implications for immunity in type 2 inflammatory disorders.
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