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 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 IL4R alpha. In the absence of IL4R alpha 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 IL4R alpha signaling may be potential targets for further study and therapeutic targeting in patients with EGPA.

Automated summary

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare and poorly understood disease characterized by elevated levels of TSLP, IL-25, and soluble ST2 in patients, alongside reduced circulating ILC2s. A mouse model study revealed the important roles of IL-33, ILC2s, and IL4R alpha signaling in the pathogenesis of EGPA.