title: IL-17 mediates immunopathology in the absence of IL-10 following Leishmania major infection.
abstract: Leishmaniasis, resulting from infection with the protozoan parasite Leishmania, consists of a wide spectrum of clinical manifestations, from healing cutaneous lesions to fatal visceral infections. A particularly severe form of cutaneous leishmaniasis, termed mucosal leishmaniasis, exhibits decreased IL-10 levels and an exaggerated inflammatory response that perpetuates the disease. Using a mouse model of leishmaniasis, we investigated what cytokines contribute to increased pathology when IL-10-mediated regulation is absent. Leishmania major infected C57BL/6 mice lacking IL-10 regulation developed larger lesions than controls, but fewer parasites. Both IFN-γ and IL-17 levels were substantially elevated in mice lacking the capacity to respond to IL-10. IFN-γ promoted an increased infiltration of monocytes, while IL-17 contributed to an increase in neutrophils. Surprisingly, however, we found that IFN-γ did not contribute to increased pathology, but instead regulated the IL-17 response. Thus, blocking IFN-γ led to a significant increase in IL-17, neutrophils and disease. Similarly, the production of IL-17 by cells from leishmaniasis patients was also regulated by IL-10 and IFN-γ. Additional studies found that the IL-1 receptor was required for both the IL-17 response and increased pathology. Therefore, we propose that regulating IL-17, possibly by downregulating IL-1β, may be a useful approach for controlling immunopathology in leishmaniasis.
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Claudia
authors.initials: C
authors.lastname: Gonzalez-Lombana
authors.forename: Ciara
authors.initials: C
authors.lastname: Gimblet
authors.forename: Olivia
authors.initials: O
authors.lastname: Bacellar
authors.forename: Walker W
authors.initials: WW
authors.lastname: Oliveira
authors.forename: Sara
authors.initials: S
authors.lastname: Passos
authors.forename: Lucas P
authors.initials: LP
authors.lastname: Carvalho
authors.forename: Michael
authors.initials: M
authors.lastname: Goldschmidt
authors.forename: Edgar M
authors.initials: EM
authors.lastname: Carvalho
authors.forename: Phillip
authors.initials: P
authors.lastname: Scott
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000097:blood / Q000276:immunology; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics; D020381:Interleukin-17 / Q000097:blood / Q000276:immunology*; D053583:Interleukin-1beta / Q000378:metabolism; D018320:Leishmania major / Q000472:pathogenicity / Q000502:physiology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D020556:Neutrophil Infiltration
chemical_list: D020381:Interleukin-17; D053583:Interleukin-1beta; D016753:Interleukin-10; D007371:Interferon-gamma
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