TY - JOUR
T1 - A role for IL-33-activated ILC2s in eosinophilic vasculitis
AU - Kotas, Maya E.
AU - Dion, Jérémie
AU - Dyken, Steven Van
AU - Ricardo-Gonzalez, Roberto R.
AU - Danel, Claire J.
AU - Taillé, Camille
AU - Mouthon, Luc
AU - Locksley, Richard M.
AU - Terrier, Benjamin
N1 - Funding Information:
This work was supported by the NIH (HL107202 to RML, and F32-HL140868 and T32-HL007185 to MEK), the A.P. Giannini Foundation, the Howard Hughes Medical Institute, the Sandler Asthma Basic Research Center at UCSF, the UCSF Diabetes Research Center, the Fonds IMMUNOV for Innovation in Immunopathology, Groupe Pasteur Mutualité, Fondation Monahan, the Fulbright Commission, the Philippe Foundation, Assistance Publique-Hôpitaux de Paris, and Paris Descartes University.
Publisher Copyright:
© 2021, Kotas et al.
PY - 2021/6/22
Y1 - 2021/6/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85108447364&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.143366
DO - 10.1172/jci.insight.143366
M3 - Article
C2 - 33974563
AN - SCOPUS:85108447364
SN - 2379-3708
VL - 6
JO - JCI insight
JF - JCI insight
IS - 12
M1 - e143366
ER -