Inibição farmacológica da via de sinalização Notch preserva parcialmente as populações de células caliciformes e Paneth no intestino delgado e melhora os aspectos histopatológicos no fígado e pulmão no modelo experimental de toxoplasmose aguda

Abstract

Notch signaling pathway plays a crucial role in cellular fate across species by regulating the intestinal stem cell fate for maintenance, proliferation and differentiation to secretory or absorptive lineage. Immune processes as differentiation of Th cell and inflammation process are also related to the Notch pathway. Toxoplasma gondii infection mice model is considered a relevant prototype for study inflammatory and immune response. Although Notch pathway is crucial for immune response, little is known about its relation with protozoan infections as toxoplasmosis. The aim of this study was to evaluated the inhibition of Notch pathway by dibenzazepine (DBZ), a γ-secretase inhibitor, using an acute toxoplasmosis mice model. For this propose, C57BL/6 mice were treated 4 days before oral infection with cysts of ME-49 T. gondii strain and the small intestine, liver and lungs were analyzed for parasitism, immunological and histological parameters. By studying the small intestine, T. gondii infection impaired the Hes1 and Math1, but not Notch1 expression. When animals were treated with DBZ and infected with T. gondii, small intestine length was preserved, goblet and Paneth cell numbers were partially recovered when compared only with the infected group, however the parasitism and pathology were not altered. On the contrary, in the liver and lungs, the previous DBZ-treatment diminished the parasitism and inflammatory alterations in the infected animals. Inhibition of the Notch pathway did not interfere on the high production of IFN-γ, TNF, IL-6 e IL-10 systemically induce by T. gondii infection, still IL-17 and IL-4 were increase. Our results highlight that Hes1 and Math1 are targets of T. gondii infection, without affecting Notch-1 expression in the small intestine. Moreover, Notch pathway inhibition results in different parasitological and inflammatory outcomes depending on the organ analyzed, being beneficial the inhibition of the γ-secretase complex for the extra intestinal organs, like lungs and liver.