title: Combinatorial targeting of TSLP, IL-25, and IL-33 in type 2 cytokine-driven inflammation and fibrosis.
abstract: Thymic stromal lymphopoietin (TSLP), interleukin-25 (IL-25), and IL-33 are important initiators of type 2-associated mucosal inflammation and immunity. However, their role in the maintenance of progressive type 2 inflammation and fibrosis is much less clear. Using chronic models of helminth infection and allergic lung inflammation, we show that collective disruption of TSLP, IL-25, and IL-33 signaling suppresses chronic and progressive type 2 cytokine-driven inflammation and fibrosis. In a schistosome lung granuloma model or during chronic Schistosoma mansoni infection in the liver, individual ablation of TSLP, IL-25, or IL-33/ST2 had no impact on the development of IL-4/IL-13-dependent inflammation or fibrosis. However, significant reductions in granuloma-associated eosinophils, hepatic fibrosis, and IL-13-producing type 2 innate lymphoid cells (ILC2s) were observed when signaling of all three mediators was simultaneously disrupted. Combined blockade through monoclonal antibody (mAb) treatment also reduced IL-5 and IL-13 expression during primary and secondary granuloma formation in the lungs. In a model of chronic house dust mite-induced allergic lung inflammation, combined mAb treatment did not decrease established inflammation or fibrosis. TSLP/IL-33 double-knockout mice treated with anti-IL-25 mAb during priming, however, displayed decreased inflammation, mucus production, and lung remodeling in the chronic phase. Together, these studies reveal partially redundant roles for TSLP, IL-25, and IL-33 in the maintenance of type 2 pathology and suggest that in some settings, early combined targeting of these mediators is necessary to ameliorate progressive type 2-driven disease.
authors.affiliation: Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Vannella
authors.affiliation: Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Thirumalai R
authors.initials: TR
authors.lastname: Ramalingam
authors.affiliation: Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Tissue Fibrosis and Repair Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Lee A
authors.initials: LA
authors.lastname: Borthwick
authors.affiliation: Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Luke
authors.initials: L
authors.lastname: Barron
authors.affiliation: Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Hart
authors.affiliation: Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Thompson
authors.affiliation: Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kristen N
authors.initials: KN
authors.lastname: Kindrachuk
authors.affiliation: Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Biomedical Research Institute, Rockville, MD 20852, USA.
authors.forename: Allen W
authors.initials: AW
authors.lastname: Cheever
authors.affiliation: Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: White
authors.affiliation: Department of Inflammation Research, Amgen, 1201 Amgen Court West, Seattle, WA 98119, USA.
authors.forename: Alison L
authors.initials: AL
authors.lastname: Budelsky
authors.affiliation: Department of Inflammation Research, Amgen, 1201 Amgen Court West, Seattle, WA 98119, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Comeau
authors.affiliation: Department of Inflammation Research, Amgen, 1201 Amgen Court West, Seattle, WA 98119, USA.
authors.forename: Dirk E
authors.initials: DE
authors.lastname: Smith
authors.affiliation: Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. twynn@niaid.nih.gov.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Wynn
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005355:Fibrosis / Q000188:drug therapy / Q000276:immunology* / Q000628:therapy; D006099:Granuloma / Q000188:drug therapy / Q000276:immunology / Q000469:parasitology / Q000628:therapy; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology* / Q000628:therapy*; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000067596:Interleukin-33 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000469:parasitology / Q000628:therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012550:Schistosoma mansoni / Q000276:immunology / Q000472:pathogenicity; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D018793:Interleukin-13; D020381:Interleukin-17; D000067596:Interleukin-33; D015847:Interleukin-4; D000094632:Thymic Stromal Lymphopoietin