Dados do Trabalho

Título

Targeting the Hedgehog pathway is a novel therapeutic strategy for hepatosplenic schistosomiasis mansoni

Introdução

IL13 and Hedgehog (Hh) signaling pathways have both been implicated in the pathogenesis of fibrosis.

Objetivo (s)

Our aims were to determine if there is cross-talk between IL13 and Hh pathways and if Hh pathway inhibitors could be used as anti-fibrotic therapy in schistosomiasis mansoni.

Material e Métodos

Hh/IL13 signaling were investigated by qRT-PCR, immunohistochemistry and ELISA in uninfected healthy transplant donors (n=22), infected hepatointestinal schistosomiasis patients (liver granulomas, low fibrosis, n=17), infected hepatosplenic patients (advanced fibrosis and portal hypertension n=72); in Schistosoma mansoni infected mice (wild-type, IL13Rα1-/- and TKO (IL-10-/- IL12p40-/-IL13Rα2-/-) treated with anti-IL13 antibody, Hh pathway inhibitors (Vismodegib or Arsenic Trioxide (ATO) or HPI) or vehicle; in mice overexpressing IL13 (plasmid) and in human liver cells stimulated with recombinant IL13 (rIL13) and treated with STAT6 siRNA or Vismodegib.

Resultados e Conclusão

Hh signaling is upregulated in human schistosomiasis and correlates with IL13, fibrosis stage and severity of portal hypertension. Overexpression of IL13 (plasmid, infected TKO mice, rIL13) induced Hh ligand production/pathway activation; lack of IL13 signaling (IL13Rα1-/- infected mice, anti-IL13 antibody, STAT6 siRNA) implicated in reduced Hh pathway, indicating that Hh signaling is dependent on IL13. STAT6 Chromatin Immunoprecipitation assay further demonstrated that STAT6 directly bind to the promoter region and regulate the transcription of Hh ligands (Ihh, Dhh) and transcription factors (Gli1, Gli2, Gli3). Smoothened antagonist Vismodegib effectively blocked fibrosis during acute schistosomiasis but failed to inhibit Hh signaling/fibrogenesis when treatment was initiated in chronic phase due to Smoothened-independent IL13-mediated GLI2 activation. GLI2 inhibition with ATO or HPI in the chronic phase impaired Hh signaling, fibrogenesis and inflammation. Activation of the Hh pathway in schistosomiasis is highly dependent on IL13-mediated signaling. Targeting Hh pathway with GLI2 antagonists may be a novel therapeutic strategy to treat schistosomiasis fibrosis and portal hypertension.

Palavras-chave

hepatosplenic schistosomiasis mansoni, liver fibrosis, portal hypertension, Hedgehog signaling, Interleukin 13, STAT6

Agradecimentos

CNPq, CAPES,NIH