Macrophages promote progression of spasmolytic polypeptide-expressing metaplasia after acute loss of parietal cells

Gastroenterology. 2014 Jun;146(7):1727-38.e8. doi: 10.1053/j.gastro.2014.02.007. Epub 2014 Feb 15.

Abstract

Background & aims: Loss of parietal cells causes the development of spasmolytic polypeptide-expressing metaplasia (SPEM) through transdifferentiation of chief cells. In the presence of inflammation, SPEM can advance into a more proliferative metaplasia with increased expression of intestine-specific transcripts. We used L635 to induce acute SPEM with inflammation in mice and investigated the roles of inflammatory cells in the development of SPEM.

Methods: To study the adaptive immune system, Rag1 knockout, interferon-γ-deficient, and wild-type (control) mice received L635 for 3 days. To study the innate immune system, macrophages were depleted by intraperitoneal injection of clodronate liposomes 2 days before and throughout L635 administration. Neutrophils were depleted by intraperitoneal injection of an antibody against Ly6G 2 days before and throughout L635 administration. Pathology and immunohistochemical analyses were used to determine depletion efficiency, metaplasia, and proliferation. To characterize SPEM in each model, gastric tissues were collected and levels of Cftr, Dmbt1, and Gpx2 mRNAs were measured. Markers of macrophage polarization were used to identify subpopulations of macrophages recruited to the gastric mucosa.

Results: Administration of L635 to Rag1 knockout, interferon-γ-deficient, and neutrophil-depleted mice led to development of proliferative SPEM and up-regulation of intestine-specific transcripts in SPEM cells, similar to controls. However, macrophage-depleted mice given L635 showed significant reductions in numbers of SPEM cells, SPEM cell proliferation, and expression of intestine-specific transcripts, compared with control mice given L635. In mice given L635, as well as patients with intestinal metaplasia, M2 macrophages were the primary inflammatory component.

Conclusions: Results from studies of mouse models and human metaplastic tissues indicate that M2 macrophages promote the advancement of SPEM in the presence of inflammation.

Keywords: Acute Injury; CD68; Gastric Cancer; Immune Depletion.

Publication types

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

MeSH terms

  • Adaptive Immunity
  • Animals
  • Atrophy
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / immunology
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
  • Disease Models, Animal
  • Gastritis / chemically induced
  • Gastritis / genetics
  • Gastritis / immunology
  • Gastritis / metabolism*
  • Gastritis / pathology
  • Gene Expression Regulation, Neoplastic
  • Glutathione Peroxidase / genetics
  • Glutathione Peroxidase / metabolism
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Immunity, Innate
  • Inflammation Mediators / metabolism
  • Intercellular Signaling Peptides and Proteins
  • Interferon-gamma / deficiency
  • Interferon-gamma / genetics
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Male
  • Metaplasia
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mucins / genetics
  • Mucins / metabolism
  • Neutrophils / immunology
  • Neutrophils / metabolism
  • Parietal Cells, Gastric / immunology
  • Parietal Cells, Gastric / metabolism*
  • Parietal Cells, Gastric / pathology
  • Peptides / metabolism*
  • Phenotype
  • RNA, Messenger / metabolism
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / immunology
  • Stomach Neoplasms / metabolism*
  • Stomach Neoplasms / pathology
  • Up-Regulation

Substances

  • Dmbt1 protein, mouse
  • Homeodomain Proteins
  • Inflammation Mediators
  • Intercellular Signaling Peptides and Proteins
  • Mucins
  • Peptides
  • RNA, Messenger
  • spasmolytic polypeptide
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • RAG-1 protein
  • Interferon-gamma
  • Gpx2 protein, mouse
  • Glutathione Peroxidase