RETEGUI Lilia Alicia
congresos y reuniones científicas
Specific inhibition of liver tryptophan catabolism reduced the autoimmune response induced by mouse hepatitis virus
MAITE DUHALDE-VEGA, JOSÉ LUIS APARICIO, LILIA RETEGUI
Congreso; First LASID-SAI-FAIC Meeting; 2015
Background: Mice infected with mouse hepatitis virus A59 (MHV-A59) develop autoantibodies (autoAb) to liver and kidney fumarylacetoacetate hydrolase (FAH) with a concomitant release of alarmins such as uric acid and high-mobility group box protein 1 (HMGB1). Tryptophan catabolism represent an endogenous mechanism that restricts excessive immune responses, thereby preventing immunopathology. There are two key rate- limiting enzymes of tryptophan catabolism:indolamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO). We have shown that IDO inhibition enhanced hypergammaglobulinemia and liver fibrosis and severely reduced survival of MHV-infected mice. Thus, the aim of this work was to study the role of TDO on MHV-infection. A derivative of 3-(2-(pyridyl) ethenyl) indole (LM10) was used to specifically inhibit TDO activity in MHV-infected mice. Methods: Serum gammaglobulines and Ab to MHV were analized by ELISA. Western-Blot assays were used to determine anti-FAH antibodies and HMGB1 serum levels. Plasmatic uric acid, as well as transaminases activities were detected using commercial kits. Liver histopathology was also analyzed. Results: Data showed that LM10 administration decreased the hypergammaglobulinemia induced by the virus, and also suppressed HMGB1 release and anti-FAH autoAb. Neither Ab to MHV nor transaminases or uric acid release were affected in LM10-treated infected mice. Liver histology and survival analysis showed no differences between treated and non-treated animals. Conclusion: Since present results indicated that specific TDO blockage suppressed autoAb to FAH as well as polyclonal activation and HMGB1 liberation produced by MHV, we suggest that TDO inhibition has beneficial immunomodulatory effects on MHV-infected animals.