Centre for Inflammation Research, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom.
Department of Biochemistry, University of Oxford, Oxford, United Kingdom.
Elife. 2020 May 18;9:e54017. doi: 10.7554/eLife.54017.
The IL-33-ST2 pathway is an important initiator of type 2 immune responses. We previously characterised the HpARI protein secreted by the model intestinal nematode , which binds and blocks IL-33. Here, we identify Binds Alarmin Receptor and Inhibits (HpBARI) and HpBARI_Hom2, both of which consist of complement control protein (CCP) domains, similarly to the immunomodulatory HpARI and Hp-TGM proteins. HpBARI binds murine ST2, inhibiting cell surface detection of ST2, preventing IL-33-ST2 interactions, and inhibiting IL-33 responses in vitro and in an in vivo mouse model of asthma. In infection, ST2 detection is abrogated in the peritoneal cavity and lung, consistent with systemic effects of HpBARI. HpBARI_Hom2 also binds human ST2 with high affinity, and effectively blocks human PBMC responses to IL-33. Thus, we show that blocks the IL-33 pathway via both HpARI which blocks the cytokine, and also HpBARI which blocks the receptor.
IL-33-ST2 通路是 2 型免疫反应的重要启动子。我们之前对模型肠道线虫 分泌的 HpARI 蛋白进行了表征，该蛋白可结合并阻断 IL-33。在这里，我们鉴定了 Binds Alarmin Receptor and Inhibits (HpBARI) 和 HpBARI_Hom2，它们都由补体控制蛋白 (CCP) 结构域组成，与免疫调节 HpARI 和 Hp-TGM 蛋白相似。HpBARI 结合小鼠 ST2，抑制 ST2 的细胞表面检测，阻止 IL-33-ST2 相互作用，并抑制体外和体内哮喘小鼠模型中的 IL-33 反应。在 感染中，腹腔和肺部的 ST2 检测被阻断，这与 HpBARI 的全身作用一致。HpBARI_Hom2 也与人类 ST2 具有高亲和力结合，并有效阻断人类 PBMC 对 IL-33 的反应。因此，我们表明 通过 HpARI 阻断细胞因子，通过 HpBARI 阻断受体，均可阻断 IL-33 通路。
