title: Immature myeloid progenitors promote disease progression in a mouse model of Barrett's-like metaplasia.
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.
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Jianping
authors.initials: J
authors.lastname: Kong
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Sai
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Mary Ann S
authors.initials: MA
authors.lastname: Crissey
authors.affiliation: Department of Pathology, Temple University, Philadelphia, PA, USA.
authors.forename: Nirag
authors.initials: N
authors.lastname: Jhala
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Gary W
authors.initials: GW
authors.lastname: Falk
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Ginsberg
authors.affiliation: Division of Gastroenterology, Columbia University, New York, NY, USA.
authors.forename: Julian A
authors.initials: JA
authors.lastname: Abrams
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakagawa
authors.affiliation: Division of Gastroenterology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Wang
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Rustgi
authors.affiliation: Division of Gastroenterology, Columbia University, New York, NY, USA.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Lynch
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001471:Barrett Esophagus / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000071616:CDX2 Transcription Factor; D004195:Disease Models, Animal; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004941:Esophagitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D008679:Metaplasia / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000473:pathology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000071616:CDX2 Transcription Factor; C487514:Cdx2 protein, mouse; D018398:Homeodomain Proteins; D053583:Interleukin-1beta; D014157:Transcription Factors
keywords: Barrett’s esophagus; IL-17; IL-1β; S100A9; myeloid-derived suppressor cells (MDSC)