Megan Osbourn 1 , 9 , Dinesh C. Soares 1 , 9 , Francesco Vacca 1 , 9 , E. Suzanne Cohen 2 , Ian C. Scott 2 , William F. Gregory 1 , Danielle J. Smyth 3 , 4 , Matilda Toivakka 1 , 3 , Andrea M. Kemter 3 , 4 , Thierry le Bihan 5 , Martin Wear 6 , Dennis Hoving 4 , Kara J. Filbey 3 , James P. Hewitson 3 , 7 , Holly Henderson 1 , Andrea Gonzàlez-Cìscar 1 , 3 , Claire Errington 1 , Sonja Vermeren 1 , Anne L. Astier 1 , William A. Wallace 8 , Jürgen Schwarze 1 , Alasdair C. Ivens 3 , Rick M. Maizels 3 , 4 , 10 , ∗ , Henry J. McSorley 1 , 3 , 10 , 11 , ∗∗
17 October 2017
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.
Osbourn et al identified HpARI, a protein secreted by a helminth parasite that is capable of suppressing allergic responses. HpARI binds to IL-33 (a critical inducer of allergy) and nuclear DNA, preventing the release of IL-33 from necrotic epithelial cells.