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: Claudia Gonzalez-Lombana, Ciara Gimblet, Olivia Bacellar, Walker W Oliveira, Sara Passos, Lucas P Carvalho, Michael Goldschmidt, Edgar M Carvalho, Phillip Scott
• Journal: PLoS pathogens (PLoS Pathog) Vol. 9 Issue 3 Pg. e1003243 (Mar 2013) ISSN: 1553-7374 [Electronic] United States
• PMID: 23555256 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Interleukin-17
• Interleukin-1beta
• Interleukin-10
• Interferon-gamma

Topics

• Animals
• Disease Models, Animal
• Down-Regulation
• Female
• Humans
• Interferon-gamma (blood, immunology)
• Interleukin-10 (deficiency, genetics)
• Interleukin-17 (blood, immunology)
• Interleukin-1beta (metabolism)
• Leishmania major (pathogenicity, physiology)
• Leishmaniasis, Cutaneous (immunology, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Monocytes (immunology)
• Neutrophil Infiltration