MicroRNA155 Plays a Critical Role in the Pathogenesis of Cutaneous Leishmania major Infection by Promoting a Th2 Response and Attenuating Dendritic Cell Activity

摘要

Interferon (IFN)-gamma is indispensable in the resolution of cutaneous leishmaniasis (CL), while the Th2 cytokines IL-4, IL-10, and IL-13 mediate susceptibility. A recent study found that miR155, which promotes CD4(+) Th1 response and IFN-gamma production, is dispensable in the control of Leishmania donovani infection. Here, the role of miR155 in CL caused by L. major was investigated using miR155-deficient (miR155(-/-)) mice. Infection was controlled significantly quicker in the miR155(-/-) mice than in their wild-type (WT) counterparts, indicating that miR155 contributes to the pathogenesis of CL. Faster resolution of infection in miR155(-/-) mice was associated with increased levels of Th1-associated IL-12 and IFN-gamma and reduced production of Th2- associated IL-4, IL-10, and IL-13. Concentrations of IFN-gamma(+)CD8(+) T cells and natural killer cells in draining lymph nodes were significantly higher in the L. major-infected miR155(-/-) mice than in the infected WT mice, as indicated by flow-cytometry. After in vitro IFN-gamma stimulation, nitric oxide and IL-12 production were increased, IL-10 production was decreased, and parasite clearance was enhanced in L. major-infected miR155(-/-) DCs compared to those in WT DCs. Furthermore, IFN-gamma production from activated miR155(-/-) T cells was significantly enhanced in L. major-infected miR155(-/-) DCs. Together, these findings demonstrate that miR155 promotes susceptibility to CL caused by L. major by promoting Th2 response and inhibiting DC function.