Type 2 Interleukin-4 Receptor Signaling in Neutrophils Antagonizes Their Expansion and Migration during Infection and Inflammation
Type 2 Interleukin-4 Receptor Signaling in Neutrophils Antagonizes Their Expansion and Migration during Infection and Inflammation
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DOI：
10.1016/j.immuni.2016.06.025
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发表时间：
2016-07-19
期刊：
影响因子：
32.4
通讯作者：
Boyman, Onur
中科院分区：
文献类型：
--
作者：
Woytschak, Janine;Keller, Nadia;Boyman, Onur
中性粒细胞是第一个被募集到炎症和感染部位的免疫细胞。然而，过敏性疾病如特应性皮炎的患者显示皮肤中性粒细胞缺乏，并且容易发生细菌性皮肤感染，这表明过敏性炎症减少了中性粒细胞反应。在这里，我们已经表明，2型细胞标志细胞因子白细胞介素-4（IL-4）通过拮抗粒细胞集落刺激因子（G-CSF）和趋化因子受体介导的信号阻碍中性粒细胞的扩增和迁移。小鼠的皮肤细菌感染因IL-4信号传导而加剧，并因IL-4抑制而改善，每种结果均与中性粒细胞向皮肤的迁移呈负相关。同样，全身性细菌感染因IL-4活性升高而恶化，IL-4通过影响中性粒细胞中的CXCR 2-CXCR 4趋化因子信号传导来限制G-CSF诱导的中性粒细胞扩增和向组织的迁移。这些作用依赖于IL-4通过中性粒细胞上的2型IL-4受体起作用。因此，靶向IL-4可能有益于对细菌感染易感性增加的血小板减少症。
Neutrophils are the first immune cells recruited to sites of inflammation and infection. However, patients with allergic disorders such as atopic dermatitis show a paucity of skin neutrophils and are prone to bacterial skin infections, suggesting that allergic inflammation curtails neutrophil responses. Here we have shown that the type 2 cell signature cytokine interleukin-4 (IL-4) hampers neutrophil expansion and migration by antagonizing granulocyte colony-stimulating factor (G-CSF) and chemokine receptor-mediated signals. Cutaneous bacterial infection in mice was exacerbated by IL-4 signaling and improved with IL-4 inhibition, each outcome inversely correlating with neutrophil migration to skin. Likewise, systemic bacterial infection was worsened by heightened IL-4 activity, with IL-4 restricting G-CSF-induced neutrophil expansion and migration to tissues by affecting CXCR2-CXCR4 chemokine signaling in neutrophils. These effects were dependent on IL-4 acting through type 2 IL-4 receptors on neutrophils. Thus, targeting IL-4 might be beneficial in neutropenic conditions with increased susceptibility to bacterial infections.