IL-17/IL-17 Receptor Pathway-Mediated Inflammatory Response in Apostichopus japonicus Supports the Conserved Functions of Cytokines in Invertebrates
IL-17/IL-17 Receptor Pathway-Mediated Inflammatory Response in Apostichopus japonicus Supports the Conserved Functions of Cytokines in Invertebrates
复制标题
刺参中 IL-17/IL-17 受体途径介导的炎症反应支持无脊椎动物中细胞因子的保守功能
DOI：
10.4049/jimmunol.2100047
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发表时间：
2022-01-15
影响因子：
4.4
通讯作者：
Li, Chenghua
中科院分区：
文献类型：
--
作者：
Lv, Zhimeng;Guo, Ming;Li, Chenghua
炎症参与宿主对感染因子的防御，并促成许多疾病的病理生理学。IL-17是一种众所周知的促炎细胞因子，有助于脊椎动物炎症的各个方面。然而，无脊椎动物IL-17在炎症调节中的功能作用还不清楚。在本研究中，我们首先建立了一个炎症模型，在弧菌灿烂攻击的海参Apostichopus的（棘皮动物）。在脾静脉感染和体壁病变组织中观察到典型的炎性症状，如体腔细胞浸润增加、组织空泡和组织断裂。有趣的是，A.在体壁和体腔细胞中表达IL-17（AjIL-17）与炎症的发展呈正相关。给予纯化的重组AjIL-17蛋白也直接促进A. - 是的通过基因组搜索和ZDOCK预测，在海参基因组中鉴定出一种新的含有FNIII和假定TIR结构域的IL-17 R对应物。免疫共沉淀、远蛋白质印迹和激光共聚焦显微镜证实AjIL-17 R可以结合AjIL-17。随后的交联测定显示，AjIL-17二聚体通过病原体感染时二聚体AjIL-17 R的特异性结合介导炎症反应。此外，沉默AjIL-17 R显著减弱LPS或外源性AjIL-17介导的炎症反应。功能分析显示AjIL-17/AjIL-17 R通过促进A. ESTTRAF 6泛素化和p65核转位，并均匀介导体腔细胞增殖和迁移。总之，我们的结果提供了功能性证据，即IL-17是无脊椎动物和脊椎动物中的保守细胞因子，其通过IL-17-IL-17 R-TRAF 6轴与炎症调节相关。
Inflammation participates in host defenses against infectious agents and contributes to the pathophysiology of many diseases. IL-17 is a well-known proinflammatory cytokine that contributes to various aspects of inflammation in vertebrates. However, the functional role of invertebrate IL-17 in inflammatory regulation is not well understood. In this study, we first established an inflammatory model in the Vibrio splendidus-challenged sea cucumber Apostichopus japonicus (Echinodermata). Typical inflammatory symptoms, such as increased coelomocyte infiltration, tissue vacuoles, and tissue fractures, were observed in the V. splendidus-infected and diseased tissue of the body wall. Interestingly, A. japonicus IL-17 (AjIL-17) expression in the body wall and coelomocytes was positively correlated with the development of inflammation. The administration of purified recombinant AjIL-17 protein also directly promoted inflammation in A. japonicus. Through genome searches and ZDOCK prediction, a novel IL-17R counterpart containing FNIII and hypothetical TIR domains was identified in the sea cucumber genome. Coimmunoprecipitation, far-Western blotting, and laser confocal microscopy confirmed that AjIL-17R could bind AjIL-17. A subsequent cross-linking assay revealed that the AjIL-17 dimer mediates the inflammatory response by the specific binding of dimeric AjIL-17R upon pathogen infection. Moreover, silencing AjIL-17R significantly attenuated the LPS- or exogenous AjIL-17-mediated inflammatory response. Functional analysis revealed that AjIL-17/AjIL-17R modulated inflammatory responses by promoting A. japonicus TRAF6 ubiquitination and p65 nuclear translocation and evenly mediated coelomocyte proliferation and migration. Taken together, our results provide functional evidence that IL-17 is a conserved cytokine in invertebrates and vertebrates associated with inflammatory regulation via the IL-17-IL-17R-TRAF6 axis.