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

Petersen CP, Weis VG, Nam KT, Sousa JF, Fingleton B, Goldenring JR
Gastroenterology. 2014 146 (7): 1727-38.e8

PMID: 24534633 · PMCID: PMC4035414 · DOI:10.1053/j.gastro.2014.02.007

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.

Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

MeSH Terms (32)

Adaptive Immunity Animals Atrophy Calcium-Binding Proteins Cell Proliferation Cell Transformation, Neoplastic Cystic Fibrosis Transmembrane Conductance Regulator Disease Models, Animal DNA-Binding Proteins Gastritis Gene Expression Regulation, Neoplastic Glutathione Peroxidase Homeodomain Proteins Immunity, Innate Inflammation Mediators Intercellular Signaling Peptides and Proteins Interferon-gamma Macrophages Male Metaplasia Mice Mice, Inbred C57BL Mice, Knockout Mucins Neutrophils Parietal Cells, Gastric Peptides Phenotype RNA, Messenger Stomach Neoplasms Tumor Suppressor Proteins Up-Regulation

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