1. A role for IL-33-activated ILC2s in eosinophilic vasculitis
- Author
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Kotas, Maya E, Dion, Jérémie, Van Dyken, Steven, Ricardo-Gonzalez, Roberto R, Danel, Claire J, Taillé, Camille, Mouthon, Luc, Locksley, Richard M, and Terrier, Benjamin
- Subjects
Biomedical and Clinical Sciences ,Immunology ,Lung ,Rare Diseases ,2.1 Biological and endogenous factors ,Cardiovascular ,Animals ,Autoimmunity ,Churg-Strauss Syndrome ,Disease Models ,Animal ,Humans ,Immunity ,Innate ,Interleukin-33 ,Lymphocytes ,Mice ,Mouse models ,Rheumatology ,Vasculitis ,Biomedical and clinical sciences ,Health sciences - Abstract
Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare but serious disease with poorly understood mechanisms. Here, we report that patients with EGPA have elevated levels of TSLP, IL-25, and soluble ST2, which are well-characterized cytokine "alarmins" that activate or modulate type 2 innate lymphoid cells (ILC2s). Patients with active EGPA have a concurrent reduction in circulating ILC2s, suggesting a role for ILC2s in the pathogenesis of this disease. To explore the mechanism of these findings in patients, we established a model of EGPA in which active vasculitis and pulmonary hemorrhage were induced by IL-33 administration in predisposed, hypereosinophilic mice. In this model, induction of pulmonary hemorrhage and vasculitis was dependent on ILC2s and signaling through IL4Rα. In the absence of IL4Rα or STAT6, IL-33-treated mice had less vascular leak and pulmonary edema, less endothelial activation, and reduced eotaxin production, cumulatively leading to a reduction of pathologic eosinophil migration into the lung parenchyma. These results offer a mouse model for use in future mechanistic studies of EGPA, and they suggest that IL-33, ILC2s, and IL4Rα signaling may be potential targets for further study and therapeutic targeting in patients with EGPA.
- Published
- 2021