IL-17 mediates immunopathology in the absence of IL-10 following Leishmania major infection

• Published in: PLoS pathogens 2013-03, Vol.9 (3), p.e1003243-e1003243
• Main Authors: Gonzalez-Lombana, Claudia, Gimblet, Ciara, Bacellar, Olivia, Oliveira, Walker W, Passos, Sara, Carvalho, Lucas P, Goldschmidt, Michael, Carvalho, Edgar M, Scott, Phillip
• Format: Article
• Language: English
• Subjects: Animals; Biology; Cytokines; Disease Models, Animal; Down-Regulation; Experiments; Female; Flow cytometry; Health aspects; Humans; Immunopathology; Infections; Interferon-gamma - blood; Interferon-gamma - immunology; Interleukin-10 - deficiency; Interleukin-10 - genetics; Interleukin-17 - blood; Interleukin-17 - immunology; Interleukin-1beta - metabolism; Interleukins; Leishmania major - pathogenicity; Leishmania major - physiology; Leishmaniasis; Leishmaniasis, Cutaneous - immunology; Leishmaniasis, Cutaneous - metabolism; Leishmaniasis, Cutaneous - pathology; Medicine; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes - immunology; Neutrophil Infiltration; Nitric oxide; Parasites; Parasitic diseases; Pathology; Physiological aspects; Rodents; Tropical diseases; Veterinary Science
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1003243

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.