Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis

Immunity. 2013 Aug 22;39(2):357-71. doi: 10.1016/j.immuni.2013.07.018. Epub 2013 Aug 15.


Liver fibrosis is a consequence of chronic liver diseases and thus a major cause of mortality and morbidity. Clinical evidence and animal studies suggest that local tissue homeostasis is disturbed due to immunological responses to chronic hepatocellular stress. Poorly defined stress-associated inflammatory networks are thought to mediate gradual accumulation of extracellular-matrix components, ultimately leading to fibrosis and liver failure. Here we have reported that hepatic expression of interleukin-33 (IL-33) was both required and sufficient for severe hepatic fibrosis in vivo. We have demonstrated that IL-33's profibrotic effects related to activation and expansion of liver resident innate lymphoid cells (ILC2). We identified ILC2-derived IL-13, acting through type-II IL-4 receptor-dependent signaling via the transcription factor STAT6 and hepatic stellate-cell activation, as a critical downstream cytokine of IL-33-dependent pathologic tissue remodeling and fibrosis. Our data reveal key immunological networks implicated in hepatic fibrosis and support the concept of modulation of IL-33 bioactivity for therapeutic purposes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Cell Proliferation
  • Cells, Cultured
  • Hepatic Stellate Cells / metabolism
  • Inflammation
  • Interleukin-13 / metabolism
  • Interleukin-33
  • Interleukins / immunology
  • Interleukins / metabolism*
  • Liver / cytology
  • Liver / immunology
  • Liver / metabolism*
  • Liver Cirrhosis / immunology*
  • Lymphocyte Activation
  • Lymphocytes / immunology
  • Lymphocytes / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Interleukin-4, Type II / metabolism
  • STAT6 Transcription Factor / metabolism
  • Signal Transduction


  • Il33 protein, mouse
  • Interleukin-13
  • Interleukin-33
  • Interleukins
  • Receptors, Interleukin-4, Type II
  • STAT6 Transcription Factor
  • Stat6 protein, mouse