immunology of infectious and parasitic diseases - XXXVII Congress ...

CRITICAL ROLE OF IL-17 IN THE CONTROL OF Leishmania infantum
INFECTION THROUGH THE MODULATION OF NITRIC OXIDE
PRODUCTION
Manuela S. L. Nascimento 1 , Vanessa Carregaro 1 , Djalma S. L. Júnior 1 , Diego L.
Costa 1 , Laís A. Sacramento 1 , Fabrício Dias 1 , Dario Zamboni 1 , Marcos A.
Rossi 1 , Amélia de Jesus 2 , Roque P. Almeida 2 , João S. Silva 1 .
1 – School of Medicine of Ribeirão Preto. São Paulo, Brazil – USP
2 – Biological and Health Science Center. Aracaju, Sergipe, Brazil – UFS.
E-mail: manuelasales@usp.br
Introduction: Although IL-17 is involved in host defense against several
pathogens, its function during Leishmania infantum infection, the etiologic agent
of visceral leishmaniasis (VL) in Brazil, is unknown. Our aim was to evaluate
whether IL-17 producing cells participates in the host immune response against
L. infantum and such mechanisms involved. Methods and Results: Our results
showed that L. infantum induces an up regulation of tgf-β (7 times), il-1β (1.7
times), il-6 (2.3 times), and il-23p19 (2.5 times) mRNA expression by infectedbone
marrow-derived dendritic cells (BMDC). In addition, we detected an up
regulation of IL-17 production by lymphocytes co-cultured with infected-BMCDs.
In fact, in vivo, we observed the IL-17 production in the liver (1300 pg/mL) and
spleen (145 pg/mL) of C57BL/6 WT infected mice, being peaked at the 4 th and
6 th weeks after infection. Furthermore, IL-17R -/- mice fail to kill the parasite and
showed lower hepatosplenomegaly than WT mice. In accordance, a lower
inflammatory infiltrate was observed in IL-17R -/- animals as a consequence of
significant lesser expression of cxcl10, cxcr3, ccl5 and ccr5 in the liver and
spleen, when compared to WT mice. Interestingly, an up regulation of ccl17 and
ccr4 was observed in knockout animals. In agreement, IL-17R -/- mice had an
increase on Foxp3 and IL-10 expression in the site of infection. Corroborating
these data, IL-17 production was 3 times potentiated in IL-10 -/- infected mice,
which were more resistant to infection when compared to WT. Besides, in the
absence of IL-17R a smaller expression of IFN-γ, Tbet and iNOS was detected
in the liver and spleen. Indeed, IL-17R -/- infected-macrophages showed a
deficiency in the NO production. The stimulus with only IL-17 in WT infectedmacrophage
increase the NO amounts, moreover, IL-17 acts synergistically
with IFN-γ potentiating the NO production and the macrophage leishmanicidal
capacity. The mechanism by which IL-17 production is regulated involves both
caspase-1, that potentiates its production, and RIP2, that inhibits. Conclusion: