A role for IL-33-activated ILC2s in eosinophilic vasculitis.

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 sST2, 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 are induced by IL-33 administration in predisposed, hypereosinophilic mice. In this model, induction of pulmonary hemorrhage and vasculitis is dependent on ILC2s and signaling through IL4Ra. In the absence of IL4Ra or STAT6, IL-33-treated mice have 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 suggest that IL-33, ILC2s and IL4Ra signaling may be potential targets for further study and therapeutic targeting in patients with EGPA.