Department of Immunology, University Hospital Zurich, Zurich, Switzerland.
Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Kreuzlingen, Switzerland.
J Allergy Clin Immunol. 2019 Jul;144(1):267-279.e4. doi: 10.1016/j.jaci.2019.01.042. Epub 2019 Feb 12.
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.
2 型免疫有助于抵抗寄生虫、毒液和毒素，但中性粒细胞在 2 型免疫反应中的作用和调节仍存在争议。蠕虫模型表明中性粒细胞有助于 2 型免疫，而在 2 型炎症性疾病（如哮喘）中，中性粒细胞与疾病严重程度增加有关。
我们旨在评估典型的 2 型细胞因子 IL-4 和 IL-13 对人中性粒细胞的影响。
从外周血中评估人中性粒细胞在有无 IL-4 或 IL-13 的情况下：（1）IL-4 受体亚基的表达，（2）中性粒细胞胞外陷阱（NET）的形成，（3）在体外和人源化小鼠中向 CXCL8 的迁移，以及（4）CXCR1、CXCR2 和 CXCR4 的表达，以及（5）在非过敏与过敏患者中。
人中性粒细胞表达两种类型的 IL-4 受体，其通过 IL-4 或 IL-13 的刺激会降低其形成 NET 和向 CXCL8 体外迁移的能力。同样，与对照值相比，在 IL-4 刺激的人中性粒细胞中，NOD-scid-Il2rg 小鼠体内的趋化性降低。这些作用伴随着 CXCL8 结合趋化因子受体 CXCR1 和 CXCR2 在人中性粒细胞上的下调在体外受 IL-4 或 IL-13 刺激时。来自过敏患者的中性粒细胞的体外分析或来自非过敏患者的中性粒细胞暴露于体外的过敏供体血清会损害其 NET 形成和向 CXCL8 的迁移，从而模拟 IL-4/IL-13 刺激的中性粒细胞。
人中性粒细胞中的 IL-4 受体信号转导会影响几种中性粒细胞效应功能，这对 2 型炎症性疾病中的免疫具有重要意义。
