Neutrophil Necroptosis Is Triggered by Ligation of Adhesion Molecules following GM-CSF Priming
Neutrophil Necroptosis Is Triggered by Ligation of Adhesion Molecules following GM-CSF Priming
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DOI：
10.4049/jimmunol.1600051
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发表时间：
2016-11-15
影响因子：
4.4
通讯作者：
Simon, Hans-Uwe
中科院分区：
文献类型：
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作者：
Wang, Xiaoliang;He, Zhaoyue;Simon, Hans-Uwe
细胞凋亡是生理和炎症条件下中性粒细胞死亡的最常见形式。然而，也观察到非凋亡性中性粒细胞死亡的形式。在目前的研究中，我们报告说，人类中性粒细胞发生坏死性凋亡后，暴露于GM-CSF，随后连接的粘附受体，如CD44，CD11b，CD18，或CD15。使用药理学方法，我们证明了受体相互作用蛋白激酶-3（RIPK3）-中性粒细胞中的混合谱系激酶样（MLKL）信号通路的存在，在这些治疗后，首先激活p38 MAPK和PI3K，最终导致产生高水平的活性氧（ROS）。所有这些步骤都是发生坏死性凋亡所必需的。此外，我们发现MLKL在炎症条件下在体内中性粒细胞中发生磷酸化。这种新发现的中性粒细胞坏死途径意味着靶向粘附分子可能有利于预防嗜中性粒细胞炎症反应中疾病的恶化。
Apoptosis is the most common form of neutrophil death under both physiological and inflammatory conditions. However, forms of nonapoptotic neutrophil death have also been observed. In the current study, we report that human neutrophils undergo necroptosis after exposure to GM-CSF followed by the ligation of adhesion receptors such as CD44, CD11b, CD18, or CD15. Using a pharmacological approach, we demonstrate the presence of a receptor-interacting protein kinase-3 (RIPK3)-a mixed lineage kinaselike (MLKL) signaling pathway in neutrophils which, following these treatments, first activates p38 MAPK and PI3K, that finally leads to the production of high levels of reactive oxygen species (ROS). All these steps are required for necroptosis to occur. Moreover, we show that MLKL undergoes phosphorylation in neutrophils in vivo under inflammatory conditions. This newly identified necrosis pathway in neutrophils would imply that targeting adhesion molecules could be beneficial for preventing exacerbation of disease in the neutrophilic inflammatory response.