Abscence of Caspase1 favours a T helper 2-like response and protects mice from liver damage during acute Trypanosoma cruzi infection

PAROLI, AUGUSTO FABIÁN; CANO, ROXANA; RIZZO, SABRINA; GONZALEZ, PATRICIA VERÓNICA; GEA, SUSANA ELBA

Mar del Plata

Congreso; LXIV Reunión anual de la Sociedad argentina de inmunología; 2016

Sociedad Argentina de Inmunología

Background: Caspase-1 activated through formation of an inflammasome cleaves the pro-cytokines IL1β and IL18 and triggers pyroptosis. Previously, we demonstrated an increase of IL1β+F4/80+ hepatic leukocytes associated with an up-regulation of TLR9 and NLRP3 innate immune receptors of T. cruzi infected WT mice. NLRP3 inflammasome receptor modulates the expansion of different lymphocyte subpopulations. Here, we study the role of Caspase-1/11 on plasmatic GPT activity, inflammatory cytokine levels, expansion of CD4+ lymphocytes and production of reactive oxygen species (ROS) and nitric oxide (NO) by F4/80 hepatic macrophages during acute T. cruzi infection.Methods: Male C57BL/6 WT, nlrp3-/- and casp1/11-/- mice were infected with T. cruzi (1000 i.p. injected-Tulahuen strain). IL1R and IL18R expression on and production of intracellular cytokines (IL4, IL10, IL17 and IFNγ) in hepatic CD4+ T lymphocytes, as well as the detection of ROS and NO in hepatic F4/80+ cells were evaluated by flow cytometry at 14 and 21 days post infection (dpi).Results: During acute infection, Casp1/11-/- mice showed higher parasitemia but lower hepatic leukocyte infiltration compared to WT mice. Although F4/80+ hepatic cells were augmented, they showed a decreased TLR9 expression and intracellular IL10. Also, these macrophages exhibited an increased ROS and NO production. As expected, the number of IL1R+ and IL18R+CD4+ T lymphocytes was strongly diminished. Interestingly, IL4+CD4+ T cells were markedly increased while IL17+ or IL10+CD4+ cells were reduced vs. WT. Moreover, plasmatic levels of IL1β, IFNγ, IL6 and IL10 were diminished and GPT activity was slightly increased in Casp-1 KO mice.Conclusion: The absence of Casp1 during acute infection showed a diminished inflammatory response in infiltrating hepatic leukocytes associated with a Th2-like profile. Accordingly, the lower plasmatic GPT activity and inflammatory cytokine levels suggest a lesser hepatic damage compared to infected WT mice.