Control of inflammation by stromal Hedgehog pathway activation restrains colitis

John J. Lee, Michael E. Rothenberg, E. Scott Seeley, Bryan Zimdahl, Sally Kawano, Wan Jin Lu, Kunyoo Shin, Tomoyo Sakata-Kato, James K. Chen, Maximilian Diehn, Michael F. Clarke, Philip A. Beachy

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Inflammation disrupts tissue architecture and function, thereby contributing to the pathogenesis of diverse diseases; the signals that promote or restrict tissue inflammation thus represent potential targets for therapeutic intervention. Here, we report that genetic or pharmacologic Hedgehog pathway inhibition intensifies colon inflammation (colitis) in mice. Conversely, genetic augmentation of Hedgehog response and systemic small-molecule Hedgehog pathway activation potently ameliorate colitis and restrain initiation and progression of colitis-induced adenocarcinoma. Within the colon, the Hedgehog protein signal does not act directly on the epithelium itself, but on underlying stromal cells to induce expression of IL-10, an immune-modulatory cytokine long known to suppress inflammatory intestinal damage. IL-10 function is required for the full protective effect of small-molecule Hedgehog pathway activation in colitis; this pharmacologic augmentation of Hedgehog pathway activity and stromal IL-10 expression are associated with increased presence of CD4+ Foxp3+ regulatory T cells. We thus identify stromal cells as cellular coordinators of colon inflammation and suggest their pharmacologic manipulation as a potential means to treat colitis.

Original languageEnglish (US)
Pages (from-to)E7545-E7553
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number47
DOIs
StatePublished - Nov 22 2016
Externally publishedYes

Keywords

  • Colitis
  • Colon cancer
  • Hedgehog signaling
  • Inflammatory bowel disease
  • Interleukin-10

ASJC Scopus subject areas

  • General

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  • Cite this

    Lee, J. J., Rothenberg, M. E., Seeley, E. S., Zimdahl, B., Kawano, S., Lu, W. J., Shin, K., Sakata-Kato, T., Chen, J. K., Diehn, M., Clarke, M. F., & Beachy, P. A. (2016). Control of inflammation by stromal Hedgehog pathway activation restrains colitis. Proceedings of the National Academy of Sciences of the United States of America, 113(47), E7545-E7553. https://doi.org/10.1073/pnas.1616447113