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IL-25 and Type 2 Innate Lymphoid Cells Induce Pulmonary Fibrosis

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IL-25 and Type 2 Innate Lymphoid Cells Induce Pulmonary Fibrosis IL-25 and type 2 innate lymphoid cells induce pulmonary fibrosis Emily Hamsa,b, Michelle E. Armstronga,b, Jillian L. Barlowc, Sean P. Saundersa,b, Christian Schwartzd, Gordon Cookee, Ruairi J. Fahyf, Thomas B. Crottyg, Nikhil Hiranih, Robin J. Flynnc, David Voehringerd, Andrew N. J. McKenziec, Seamas C. Donnellye,i, and Padraic G. Fallona,b,j,1 aTrinity Biomedical Sciences Institute, School of Medicine, Trinity College Dublin, Dublin 2, Ireland; bNational Children’s Research Centre, Our Lady’s Children’s Hospital, Dublin 8, Ireland; cMedical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom; dDepartment of Infection Biology, Universitätsklinikum Erlangen, 91054 Erlangen, Germany; eSchool of Medicine and Medical Science, University College Dublin, Dublin 4, Ireland; fSt. James’s Hospital, Dublin 8, Ireland; gDepartment of Pathology, St. Vincent’s University Hospital, Dublin 4, Ireland; hMedical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh EH16 4SB, United Kingdom; iNational Pulmonary Fibrosis Referral Centre, St. Vincent’s University Hospital, Dublin 4, Ireland; and jInstitute of Molecular Medicine, School of Medicine, Trinity College Dublin, St. James’s Hospital, Dublin 8, Ireland Edited by Shigeo Koyasu, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan, and accepted by the Editorial Board November 15, 2013 (received for review August 26, 2013) Disease conditions associated with pulmonary fibrosis are pro- fibrosis in experimental mouse models, via the activation of IL-13– gressive and have a poor long-term prognosis with irreversible producing ILC2. We also observe increases in both IL-25 and ILC2 changes in airway architecture leading to marked morbidity and in the lung of patients with idiopathic pulmonary fibrosis (IPF). mortalities. Using murine models we demonstrate a role for in- These data suggest unique mechanisms for the generation of pul- terleukin (IL)-25 in the generation of pulmonary fibrosis. Mechanis- monary fibrosis and identify an interesting area for further research tically, we identify IL-13 release from type 2 innate lymphoid cells on the role of IL-25 and ILC2 in the treatment of pulmonary (ILC2) as sufficient to drive collagen deposition in the lungs of fibrosis. challenged mice and suggest this as a potential mechanism through Results which IL-25 is acting. Additionally, we demonstrate that in human idiopathic pulmonary fibrosis there is increased pulmonary expres- Mice Unable to Signal via IL-25 Show Decreased S. mansoni Egg- sion of IL-25 and also observe a population ILC2 in the lungs of Associated Pulmonary Fibrosis. To address the mechanistic role idiopathic pulmonary fibrosis patients. Collectively, we present an of IL-25 in pulmonary fibrosis we used the S. mansoni egg- induced pulmonary granuloma model. In mice deficient in IL-25 innate mechanism for the generation of pulmonary fibrosis, via IL-25 −/− −/− and ILC2, that occurs independently of T-cell–mediated antigen-spe- (Il25 ) and its receptor IL-17BR (Il17br ) there was smaller egg granuloma formation relative to WT mice (Fig. 1 A and C) cific immune responses. These results suggest the potential of ther- with significantly (P < 0.05) reduced pulmonary collagen de- apeutically targeting IL-25 and ILC2 for the treatment of human position and, more specifically, less fibrosis within the egg gran- fibrotic diseases. uloma of these mice (Fig. 1 B and C). In addition, in the absence of functional IL-25 there was reduced relative pulmonary ex- innate response | cytokine | therapy | inflammation pression of type 2 cytokines IL-4 and IL-13 (Fig. 1D), and re- duced expression of TGFβ (Fig. 1D). Whereas pulmonary levels isease conditions associated with pulmonary fibrosis are of IL-17A were up-regulated in response to S. mansoni eggs in Doften progressive and have a poor long-term prognosis (1). WT mice, as previously demonstrated (2), there were compara- In the context of developing new treatments for pulmonary fi- ble IL-17A levels in all groups (Fig. 1D). Regarding the re- brosis, the cytokines associated with the pathogenic milieu that duction in IL-4 expression, a cytokine shown to be important in can lead to aberrant extracellular matrix deposition are key the generation of egg-associated granuloma formation (20), in targets, in particular interleukin (IL)-13, TGF-β, and, more re- cently, IL-17A (2). However, to develop more effective thera- Significance peutics for fibrotic lung diseases a greater understanding of the pathogenesis and the underlying mechanisms that lead to pul- Abnormal damage and scarring of tissue (fibrosis) in the lungs monary fibrosis is needed (3, 4). can lead to pulmonary fibrosis. Patients that develop the var- The cytokine IL-13 was first implicated in fibrosis using ious forms of pulmonary fibrosis are difficult to treat and have profibrotic eggs from the type 2 cytokine-inducing pathogen a high level of mortality. In this study we have used mouse Schistosoma mansoni, in the presence of a soluble IL-13Rα2-Fc models to address the role of the cytokine interleukin (IL)-25 −/− fusion protein (5) and in Il13 mice (6). IL-13 is now widely and type 2 innate lymphoid cells (ILC2) in pulmonary fibrosis. In linked to a range of fibrotic conditions (7) including asthma, animal models we show a role for IL-25 and ILC2 in the gen- where IL-13 is being targeted as a therapy (8). In the context of + eration of pulmonary fibrosis. Furthermore, we have identified the cellular source of IL-13 in the generation of fibrosis, CD4 T elevated levels of IL-25 and ILC2s in the lungs of patients with helper (h) 2 cells are implicated (9). However, more recently idiopathic pulmonary fibrosis. This study provides insights on innate lymphoid cells (ILC) are emerging as an important source the factors and cells that may initiate pulmonary fibrosis in of IL-13 (10, 11). In this context, the type 2 cytokine IL-25 is humans and have therapeutic potential. implicated in the generation of the recently identified IL-13– – IMMUNOLOGY expressing ILC, termed ILC2 (11 14). Author contributions: E.H. and P.G.F. designed research; E.H., M.E.A., J.L.B., S.P.S., C.S., Recent studies have implicated IL-25 and ILC2 in the path- G.C., and R.J. Flynn performed research; G.C., R.J. Fahy, T.B.C., N.H., R.J. Flynn, D.V., A.N.J.M., ogenesis of pulmonary conditions in both murine models and hu- and S.C.D. contributed new reagents/analytic tools; E.H., M.E.A., J.L.B., S.P.S., R.J. Flynn, man conditions such as allergic asthma (12, 13, 15, 16). In murine and A.N.J.M. analyzed data; and E.H. and P.G.F. wrote the paper. studies intranasal administration of IL-25 results in evidence of The authors declare no conflict of interest. pulmonary tissue remodeling including development of perivascular This article is a PNAS Direct Submission. S.K. is a guest editor invited by the Editorial fibrosis, and intratracheal administration results in increased pul- Board. monary Th2 cytokines and airways hyper-reactivity (AHR) (17, 18), 1To whom correspondence should be addressed. E-mail: [email protected]. whereas blocking IL-25 reduces AHR severity (19). Herein we This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. describe a potential role for IL-25 in the generation of pulmonary 1073/pnas.1315854111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1315854111 PNAS | January 7, 2014 | vol. 111 | no. 1 | 367–372 Downloaded by guest on September 24, 2021 ABPBS Egg in innate type 2 responses (21, 22). However, we found no in- 4.0 * 250 * filtration of basophils into the lungs in this model (Fig. S1B); * ** * indeed, following egg challenge of basophil-deficient mice (23) 200 3.0 there was no defect in the development of pulmonary fibrosis 3 150 (Fig. S1C). 2.0 Recent studies have highlighted the role for ILCs, in particular 100 type 2 ILCs (ILC2) in helminth-associated type 2 immunity, with (mm ) 1.0 such cells potent producers of IL-13 during inflammation (11). 50 Assessment of ILC2 in the S. mansoni egg-induced model of Collagen (μg/mg) < Granuloma volume 0 0 pulmonary inflammation demonstrates a significant (P 0.01) WT Il25 -/- Il17br -/- WT Il25 -/- Il17br -/- increase in ILC2 in both the lung and mediastinal lymph node -/- (MLN) of egg-challenged WT mice, with reduced number of C WT Il25 -/- Il17br − − − − ILC2s in the lungs of egg-challenged Il25 / and Il17br / mice + (Fig. 1E). In the lungs of WT mice, the frequency of IL-13 ILC2 peaked at day 7, with expression of such cells approximately + + + fivefold higher than IL-13 CD4 T cells, with diminished IL-13 ILC2 in the absence of IL-25 (Fig. S2B), whereas in the MLN + CD4 T cells are the primary source of IL-13 in both the pres- PBS Egg ence and absence of IL-25 (Fig. S2C). D IL-4 IL-13 In addition to IL-25, ILC2 are induced by the type 2 cytokines * * 750 * 1,200 * * IL-33 and thymic stromal lymphopoietin (TSLP) (24). Although * other studies have shown that IL-33 is the more prominent cy- 500 800 tokine involved in the induction of ILC2 (25), in this model we show that whereas IL-25 is significantly (P < 0.05) up-regulated in the lungs in response to S. mansoni eggs, the levels of IL-33 pg/mg 250 400 and TSLP in the lungs are markedly lower (Fig. S3A). In addi- − − − − tion, in Il17br / , but not animals with defective IL-33 (Il1rl1 / ) − − 0 or TSLP (Tslpr / ) signaling, there was a significant defect in 0 -/- -/- WT Il25 Il17br WT Il25 -/- Il17br -/- egg-associated pulmonary collagen deposition (Fig.
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