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

IL-33/ST2 INHIBITS COXSACKIEVIRUS B5-INDUCED EXPERIMENTAL
PANCREATITIS
RENATA SESTI-COSTA 1 , GRACE KELLY DA SILVA 1 , JOSÉ LUIZ PROENÇA-
MÓDENA 1 , DANIELA CARLOS 1 , MARIA LÚCIA SILVA 1 , JOSÉ CARLOS
ALVES-FILHO 1 , FOO YEW LIEW 2 , EURICO ARRUDA-NETO 1 , JOÃO
SANTANA DA SILVA 1 .
1 Medical School of Ribeirão Preto. FMRP/USP, Ribeirão Preto, Brazil, 2 Division
of Immunology, Infection and Inflammation, University of Glasgow, Glasgow,
United Kingdom.
Introduction: Coxsackieviruses are single-stranded and positive-polarity RNA
viruses. They have a pancreatic tropism, which often leads to fulminant
pancreatitis with subsequent pancreatic insufficiency. Apart of virus
proliferation, the Th1 immune response generated to the virus is also
responsible to tissue lesion. So, modulation strategies that balance host
immune response in eliminating the virus while minimizing injury to the host
tissue is the key to treating coxsackievirus-associated pancreatitis. With this
purpose, we investigate the effect of IL-33, a type Th2 cytokine, on CVB5induced
pancreatitis. Methods and Results: Balb/c and ST2-deficient mice
were i.p infected with 10 7 TCID50 of coxsackievirus B5 (CVB5) and the course of
infection and pancreas pathology were determined. ST2 -/- mice infected with
CVB5 developed significantly more severe pancreatitis, greater weight loss and
higher viral titer compared to wild-type (WT) BALB/c mice. Conversely, WT
mice treated with recombinant IL-33 developed significantly lower viral titer and
attenuated pancreatitis. Infected ST2 -/- mice also showed reduced levels of IL-4,
mast cells, alternatively-activated macrophages (M2) and CD4 + Foxp3 +
regulatory T (Treg) cells in the pancreas. Adoptively transferred mast cells or
M2 macrophages reversed the heightened pancreatitis in the ST2 -/- mice. In
contrast anti-GITR antibody, which inhibits Treg cells, exacerbated the disease
in WT mice. Furthermore, IL-4 and Stat6-deficient mice showed similar
phenotype as the ST2 -/- mice during CVB5 infection, suggesting a role of IL-
4/Stat6 pathway in this process. Conclusion: Together, these results reveal an
unrecognized IL-33/ST2 pathway, which stimulates mast cells and the
production of IL-4 that activates Stat6. This pathway enhances the
differentiation of M2 macrophages and Treg cells, leading to the attenuation of
inflammatory pancreatitis during CVB5 infection. Our finding also suggests that
IL-33 may be a potential therapeutic agent against CVB infection.
Financial Support: CAPES, CNPq, FAEPA.