IL-17 Mediates Immunopathology in the Absence of IL-10 Following Leishmania major Infection

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. © 2013 gonzalez-lombana et al.