title: Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma.
abstract: Severe asthma is associated with the production of interleukin 17A (IL-17A). The exact role of IL-17A in severe asthma and the factors that drive its production are unknown. Here we demonstrate that IL-17A mediated severe airway hyperresponsiveness (AHR) in susceptible strains of mice by enhancing IL-13-driven responses. Mechanistically, we demonstrate that IL-17A and AHR were regulated by allergen-driven production of anaphylatoxins, as mouse strains deficient in complement factor 5 (C5) or the complement receptor C5aR mounted robust IL-17A responses, whereas mice deficient in C3aR had fewer IL-17-producing helper T cells (T(H)17 cells) and less AHR after allergen challenge. The opposing effects of C3a and C5a were mediated through their reciprocal regulation of IL-23 production. These data demonstrate a critical role for complement-mediated regulation of the IL-23-T(H)17 axis in severe asthma.
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Stephane
authors.initials: S
authors.lastname: Lajoie
authors.forename: Ian P
authors.initials: IP
authors.lastname: Lewkowich
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Clark
authors.forename: Alyssa A
authors.initials: AA
authors.lastname: Sproles
authors.forename: Krista
authors.initials: K
authors.lastname: Dienger
authors.forename: Alison L
authors.initials: AL
authors.lastname: Budelsky
authors.forename: Marsha
authors.initials: M
authors.lastname: Wills-Karp
mesh_terms: D000485:Allergens / Q000009:adverse effects; D000706:Anaphylatoxins / Q000096:biosynthesis; D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology*; D003167:Complement Activation; D015926:Complement C3a / Q000235:genetics / Q000276:immunology*; D015936:Complement C5a / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D020022:Genetic Predisposition to Disease; D018793:Interleukin-13 / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000235:genetics; D053759:Interleukin-23 / Q000276:immunology*; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D039981:Pyroglyphidae / Q000276:immunology; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D000485:Allergens; D000706:Anaphylatoxins; D016207:Cytokines; D018793:Interleukin-13; D020381:Interleukin-17; D053759:Interleukin-23; D044087:Receptor, Anaphylatoxin C5a; D015926:Complement C3a; D015936:Complement C5a
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