title: Ozone-Induced Nasal Type 2 Immunity in Mice Is Dependent on Innate Lymphoid Cells.
abstract: Epidemiological studies suggest that elevated ambient concentrations of ozone are associated with activation of eosinophils in the nasal airways of atopic and nonatopic children. Mice repeatedly exposed to ozone develop eosinophilic rhinitis and type 2 immune responses. In this study, we determined the role of innate lymphoid cells (ILCs) in the pathogenesis of ozone-induced eosinophilic rhinitis by using lymphoid-sufficient C57BL/6 mice, Rag2(-/-) mice that are devoid of T cells and B cells, and Rag2(-/-)Il2rg(-/-) mice that are depleted of all lymphoid cells including ILCs. The animals were exposed to 0 or 0.8 ppm ozone for 9 consecutive weekdays (4 h/d). Mice were killed 24 hours after exposure, and nasal tissues were selected for histopathology and gene expression analysis. ILC-sufficient C57BL/6 and Rag2(-/-) mice exposed to ozone developed marked eosinophilic rhinitis and epithelial remodeling (e.g., epithelial hyperplasia and mucous cell metaplasia). Chitinase-like proteins and alarmins (IL-33, IL-25, and thymic stromal lymphopoietin) were also increased morphometrically in the nasal epithelium of ozone-exposed C57BL/6 and Rag2(-/-) mice. Ozone exposure elicited increased expression of Il4, Il5, Il13, St2, eotaxin, MCP-2, Gob5, Arg1, Fizz1, and Ym2 mRNA in C57BL/6 and Rag2(-/-) mice. In contrast, ozone-exposed ILC-deficient Rag2(-/-)Il2rg(-/-) mice had no nasal lesions or overexpression of Th2- or ILC2-related transcripts. These results indicate that ozone-induced eosinophilic rhinitis, nasal epithelial remodeling, and type 2 immune activation are dependent on ILCs. To the best of our knowledge, this is the first study to demonstrate that ILCs play an important role in the nasal pathology induced by repeated ozone exposure.
authors.affiliation: 1 Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kumagai
authors.affiliation: 1 Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan.
authors.forename: Ryan
authors.initials: R
authors.lastname: Lewandowski
authors.affiliation: 1 Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan.
authors.forename: Daven N
authors.initials: DN
authors.lastname: Jackson-Humbles
authors.affiliation: 1 Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: 2 Howard Hughes Medical Institute and Departments of Medicine and Microbiology & Immunology, University of California, San Francisco, San Francisco, California.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Van Dyken
authors.affiliation: 1 Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan.
authors.forename: James G
authors.initials: JG
authors.lastname: Wagner
authors.affiliation: 1 Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan.
authors.forename: Jack R
authors.initials: JR
authors.lastname: Harkema
mesh_terms: D000067531:Alarmins / Q000378:metabolism; D000818:Animals; D004804:Eosinophils / Q000187:drug effects / Q000473:pathology; D007113:Immunity, Innate / Q000187:drug effects*; D007249:Inflammation / Q000150:complications / Q000473:pathology; D007378:Interleukins / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D008297:Male; D008810:Mice, Inbred C57BL; D009297:Nasal Mucosa / Q000187:drug effects / Q000276:immunology* / Q000293:injuries / Q000473:pathology; D010126:Ozone / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012220:Rhinitis / Q000150:complications / Q000276:immunology / Q000473:pathology
chemical_list: D000067531:Alarmins; D007378:Interleukins; D012333:RNA, Messenger; D010126:Ozone
keywords: eosinophilic rhinitis; innate lymphoid cells; mice; ozone