Down-regulation of microRNA-203-3p initiates type 2 pathology during schistosome infection via elevation of interleukin-33

PLoS Pathog. 2018 Mar 19;14(3):e1006957. doi: 10.1371/journal.ppat.1006957. eCollection 2018 Mar.

Abstract

The type 2 immune response is the central mechanism of disease progression in schistosomiasis, but the signals that induce it after infection remain elusive. Aberrant microRNA (miRNA) expression is a hallmark of human diseases including schistosomiasis, and targeting the deregulated miRNA can mitigate disease outcomes. Here, we demonstrate that efficient and sustained elevation of miR-203-3p in liver tissues, using the highly hepatotropic recombinant adeno-associated virus serotype 8 (rAAV8), protects mice against lethal schistosome infection by alleviating hepatic fibrosis. We show that miR-203-3p targets interleukin-33 (IL-33), an inducer of type 2 immunity, in hepatic stellate cells to regulate the expansion and IL-13 production of hepatic group 2 innate lymphoid cells during infection. Our study highlights the potential of rAAV8-mediated miR-203-3p elevation as a therapeutic intervention for fibrotic diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Down-Regulation
  • Hepatic Stellate Cells / metabolism
  • Hepatic Stellate Cells / parasitology
  • Hepatic Stellate Cells / pathology*
  • Interleukin-33 / genetics
  • Interleukin-33 / metabolism*
  • Liver / metabolism
  • Liver / parasitology
  • Liver / pathology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • MicroRNAs / genetics*
  • Schistosoma / pathogenicity*
  • Schistosomiasis / genetics
  • Schistosomiasis / metabolism
  • Schistosomiasis / parasitology
  • Schistosomiasis / pathology*

Substances

  • Il33 protein, mouse
  • Interleukin-33
  • MIRN203 microRNA, mouse
  • MicroRNAs