title: IL-17RA signaling reduces inflammation and mortality during Trypanosoma cruzi infection by recruiting suppressive IL-10-producing neutrophils.
abstract: Members of the IL-17 cytokine family play an important role in protection against pathogens through the induction of different effector mechanisms. We determined that IL-17A, IL-17E and IL-17F are produced during the acute phase of T. cruzi infection. Using IL-17RA knockout (KO) mice, we demonstrate that IL-17RA, the common receptor subunit for many IL-17 family members, is required for host resistance during T. cruzi infection. Furthermore, infected IL-17RA KO mice that lack of response to several IL-17 cytokines showed amplified inflammatory responses with exuberant IFN-γ and TNF production that promoted hepatic damage and mortality. Absence of IL-17RA during T. cruzi infection resulted in reduced CXCL1 and CXCL2 expression in spleen and liver and limited neutrophil recruitment. T. cruzi-stimulated neutrophils secreted IL-10 and showed an IL-10-dependent suppressive phenotype in vitro inhibiting T-cell proliferation and IFN-γ production. Specific depletion of Ly-6G+ neutrophils in vivo during T. cruzi infection raised parasitemia and serum IFN-γ concentration and resulted in increased liver pathology in WT mice and overwhelming wasting disease in IL-17RA KO mice. Adoptively transferred neutrophils were unable to migrate to tissues and to restore resistant phenotype in infected IL-17RA KO mice but migrated to spleen and liver of infected WT mice and downregulated IFN-γ production and increased survival in an IL-10 dependent manner. Our results underscore the role of IL-17RA in the modulation of IFN-γ-mediated inflammatory responses during infections and uncover a previously unrecognized regulatory mechanism that involves the IL-17RA-mediated recruitment of suppressive IL-10-producing neutrophils.
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología-CIBICI-CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: Jimena
authors.initials: J
authors.lastname: Tosello Boari
authors.forename: María Carolina
authors.initials: MC
authors.lastname: Amezcua Vesely
authors.forename: Daniela Andrea
authors.initials: DA
authors.lastname: Bermejo
authors.forename: Maria Cecilia
authors.initials: MC
authors.lastname: Ramello
authors.forename: Carolina Lucía
authors.initials: CL
authors.lastname: Montes
authors.forename: Hugo
authors.initials: H
authors.lastname: Cejas
authors.forename: Adriana
authors.initials: A
authors.lastname: Gruppi
authors.forename: Eva Virginia
authors.initials: EV
authors.lastname: Acosta Rodríguez
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D014355:Chagas Disease / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D053722:Receptors, Interleukin-17 / Q000276:immunology*; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000276:immunology*
chemical_list: C556062:IL10 protein, mouse; C491673:Il17ra protein, mouse; D020381:Interleukin-17; D053722:Receptors, Interleukin-17; D016753:Interleukin-10; D007371:Interferon-gamma