Infection by helminth parasites is associated with amelioration of allergic reactivity, but mechanistic insights into this association are lacking. Products secreted by the mouse parasite Heligmosomoides polygyrus suppress type 2 (allergic) immune responses through interference in the interleukin-33 (IL-33) pathway. Here, we identified H. polygyrus Alarmin Release Inhibitor (HpARI), an IL-33-suppressive 26-kDa protein, containing three predicted complement control protein (CCP) modules. In vivo, recombinant HpARI abrogated IL-33, group 2 innate lymphoid cell (ILC2) and eosinophilic responses to Alternaria allergen administration, and diminished eosinophilic responses to Nippostrongylus brasiliensis, increasing parasite burden. HpARI bound directly to both mouse and human IL-33 (in the cytokine’s activated state) and also to nuclear DNA via its N-terminal CCP module pair (CCP1/2), tethering active IL-33 within necrotic cells, preventing its release, and forestalling initiation of type 2 allergic responses. Thus, HpARI employs a novel molecular strategy to suppress type 2 immunity in both infection and allergy.

蠕虫寄生虫感染与过敏反应的改善有关，但缺乏对这种关联的机制见解。小鼠寄生虫Heligmosomoides polygyrus分泌的产物通过干扰白细胞介素 33 (IL-33) 通路来抑制 2 型（过敏性）免疫反应。在这里，我们鉴定了H. polygyrus Alarmin Release Inhibitor (HpARI)，这是一种抑制 IL-33 的 26-kDa 蛋白，包含三个预测的补体控制蛋白 (CCP) 模块。在体内，重组 HpARI 消除了 IL-33、第 2 组先天淋巴细胞 (ILC2) 和对链格孢过敏原给药的嗜酸性粒细胞反应，并减少了对巴西日圆线虫的嗜酸性粒细胞反应，增加寄生虫负担。HpARI 直接结合小鼠和人类 IL-33（在细胞因子的激活状态），也通过其 N 端 CCP 模块对 (CCP1/2) 与核 DNA 结合，将活性 IL-33 束缚在坏死细胞内，防止其释放，并阻止 2 型过敏反应的开始。因此，HpARI 采用一种新的分子策略来抑制感染和过敏中的 2 型免疫。