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.

Interleukin-10 (IL-10) Inhibits Borrelia burgdorferi-Induced IL-17 Production and Attenuates IL-17-Mediated Lyme Arthritis

“…It is important also to note that the immune pathways associated with regulation of IL-17 are complex. For example, in support of our findings, opposing functions of IL-10 and various IL-17-producing cell types have been reported in other disease models, including infections (34,35) and, importantly, arthritis (36,37). However, cells which produce both cytokines exist (32,38), and IL-10-producing regulatory T (Treg) cells have also been shown to aid in the production of Th17 cells at certain periods of development (39).…”

CD4+T Cells: Guardians of the Phagosome

“…Indeed, it was reported that mice lacking the IL-17 receptor were defective in the long-term control of M. tuberculosis infection (156). On the other hand, M. tuberculosis and Salmonella infections are controlled normally in IL-23-deficient mice, in which Th17 generation does not occur (157,158), and neutralization of IL-17 had no effect on the control of L. major infection (159). Furthermore, people with mutations that affect the expression of IL-17 or IL-17 receptor are susceptible to Candida and Staphylococcus aureus skin infections (160) but do not appear to be susceptible to the phagosomal pathogens that afflict people lacking CD4 ϩ T cells or IL-12 receptor (27,28,161).…”

IL-17A–Producing γδ T Cells Suppress Early Control of Parasite Growth by Monocytes in the Liver

“…Support for a protective role for IL-17 comes from a study showing IL-17RA-deficient C57BL/6 mice infected with L. infantum harbored higher tissue parasite burdens than wild-type (WT) control mice (23). In contrast, IL-17 promoted the progression of cutaneous leishmaniasis in susceptible mice infected with L. major (24), whereas in IL-10-deficient mice infected with L. major, IL-17 was responsible for increased Th1 cell-mediated pathology (25). In humans, a negative association with parasite-induced IL-17 production by PBMCs from patients with cutaneous leishmaniasis and muco-cutaneous leishmaniasis infected with L. braziliensis has been reported (26,27).…”