Immature myeloid progenitors promote disease progression in a mouse model of Barrett’s-like metaplasia
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Jianping Kong1, Hong Sai1, Mary Ann S. Crissey1, Nirag Jhala2, Gary W. Falk1, Gregory G. Ginsberg1, Julian A. Abrams3, Hiroshi Nakagawa1, Kenneth Wang4, Anil K. Rustgi1, Timothy C. Wang3, John P. Lynch1
1Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
2Department of Pathology, Temple University, Philadelphia, PA, USA
3Division of Gastroenterology, Columbia University, New York, NY, USA
4Division of Gastroenterology, Mayo Clinic, Rochester, MN, USA
John P. Lynch, e-mail: [email protected]
Keywords: Barrett’s esophagus, myeloid-derived suppressor cells (MDSC), IL-17, S100A9, IL-1β
Received: August 14, 2015 Accepted: October 02, 2015 Published: October 12, 2015
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.
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