Immature myeloid progenitors promote disease progression in a mouse model of Barrett's-like metaplasia

Jianping Kong, Hong Sai, Mary Ann S Crissey, Nirag Jhala, Gary W. Falk, Gregory G. Ginsberg, Julian A. Abrams, Hiroshi Nakagawa, Kenneth Ke Ning Wang, Anil K. Rustgi, Timothy C. Wang, John P. Lynch

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Cdx2, an intestine specific transcription factor, is expressed in Barrett's esophagus (BE). We sought to determine if esophageal Cdx2 expression would accelerate the onset of metaplasia in the L2-IL-1β transgenic mouse model for Barrett's-like metaplasia. The K14-Cdx2::L2-IL-1β double transgenic mice had half as many metaplastic nodules as control L2-IL-1β mice. This effect was not due to a reduction in esophageal IL-1β mRNA levels nor diminished systemic inflammation. The diminished metaplasia was due to an increase in apoptosis in the K14-Cdx2::L2-IL-1β mice. Fluorescence activated cell sorting of immune cells infiltrating the metaplasia identified a population of CD11b+Gr-1+ cells that are significantly reduced in K14-Cdx2::L2-IL-1β mice. These cells have features of immature granulocytes and have immune-suppressing capacity. We demonstrate that the apoptosis in K14-Cdx2::L2-IL-1β mice is CD8+ T cell dependent, which CD11b+Gr-1+ cells are known to inhibit. Lastly, we show that key regulators of CD11b+Gr-1+ cell development, IL-17 and S100A9, are significantly diminished in the esophagus of K14-Cdx2::L2-IL-1β double transgenic mice. We conclude that metaplasia development in this mouse model for Barrett's-like metaplasia requires suppression of CD8+ cell dependent apoptosis, likely mediated by immune-suppressing CD11b+Gr-1+ immature myeloid cells.

Original languageEnglish (US)
Pages (from-to)32980-33005
Number of pages26
JournalOncotarget
Volume6
Issue number32
DOIs
StatePublished - 2015

Keywords

  • Barrett's esophagus
  • IL-17
  • IL-1β
  • Myeloid-derived suppressor cells (MDSC)
  • S100A9

ASJC Scopus subject areas

  • Oncology

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    Kong, J., Sai, H., Crissey, M. A. S., Jhala, N., Falk, G. W., Ginsberg, G. G., Abrams, J. A., Nakagawa, H., Wang, K. K. N., Rustgi, A. K., Wang, T. C., & Lynch, J. P. (2015). Immature myeloid progenitors promote disease progression in a mouse model of Barrett's-like metaplasia. Oncotarget, 6(32), 32980-33005. https://doi.org/10.18632/oncotarget.5431