Induction of autophagy in Cx3cr1 + mononuclear cells limits IL-23/IL-22 axis-mediated intestinal fibrosis

Mucosal Immunol. 2019 May;12(3):612-623. doi: 10.1038/s41385-019-0146-4. Epub 2019 Feb 14.

Abstract

Intestinal fibrosis is an excessive proliferation of myofibroblasts and deposition of collagen, a condition frequently seen in Crohn's disease (CD). The mechanism underlying myofibroblast hyper-proliferation in CD needs to be better understood. In this report, we found that mTOR inhibitor rapamycin or mTOR deletion in CX3Cr1+ mononuclear phagocytes inhibits expression of interleukin (IL)-23, accompanied by reduced intestinal production of IL-22 and ameliorated fibrosis in the TNBS-induced fibrosis mouse model. This inhibition of IL-23 expression is associated with elevated autophagy activity. Ablating the autophagy gene Atg7 increases the expression of IL-23, leading to increased expression of IL-22 and increased fibrosis. Both induction of IL-22 and intestinal fibrosis occurred in RAG-/- mice and depletion of innate lymphoid cells (ILCs) attenuates the fibrotic reaction, suggesting that the pro-fibrotic process is independent of T and B cells. Moreover, IL-22 facilitates the transformation of fibroblasts into myofibroblasts. Finally, the fibrotic reaction was attenuated upon neutralization of either IL-23 or IL-22. Altogether, this study elucidated a signaling cascade underlying intestinal fibrosis in which altered mTOR/autophagy in CX3Cr1+ mononuclear phagocytes up-regulates the IL-23/IL-22 axis, leading to an excessive fibrotic response. Thus, our findings suggest that this cascade could be a therapeutic target for alleviation of CD fibrosis.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Neutralizing / metabolism
  • Autophagy / genetics
  • Autophagy-Related Protein 7 / genetics
  • CX3C Chemokine Receptor 1 / metabolism
  • Cells, Cultured
  • Crohn Disease / immunology*
  • Disease Models, Animal
  • Female
  • Fibrosis
  • Humans
  • Immunity, Innate
  • Interleukin-23 / immunology
  • Interleukin-23 / metabolism*
  • Interleukins / immunology
  • Interleukins / metabolism*
  • Intestines / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phagocytes / immunology*
  • Signal Transduction

Substances

  • Antibodies, Neutralizing
  • CX3C Chemokine Receptor 1
  • CX3CR1 protein, human
  • Interleukin-23
  • Interleukins
  • Autophagy-Related Protein 7
  • interleukin-22