Christine P Petersen1, Victoria G Weis1, Ki Taek Nam2, Josane F Sousa3, Barbara Fingleton4, James R Goldenring5. 1. Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee; Department of Surgery, Vanderbilt University, Nashville, Tennessee. 2. Department of Surgery, Vanderbilt University, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University, Nashville, Tennessee; Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea. 3. Department of Surgery, Vanderbilt University, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University, Nashville, Tennessee. 4. Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee. 5. Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee; Department of Surgery, Vanderbilt University, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University, Nashville, Tennessee; Nashville VA Medical Center, Nashville, Tennessee. Electronic address: jim.goldenring@vanderbilt.edu.
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.
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.
Authors: Sangho Jeong; Eunyoung Choi; Christine P Petersen; Joseph T Roland; Alessandro Federico; Rossana Ippolito; Francesco P D'Armiento; Gerardo Nardone; Osamu Nagano; Hideyuki Saya; Marco Romano; James R Goldenring Journal: United European Gastroenterol J Date: 2016-06-23 Impact factor: 4.623
Authors: Christine P Petersen; Anne R Meyer; Carlo De Salvo; Eunyoung Choi; Cameron Schlegel; Alec Petersen; Amy C Engevik; Nripesh Prasad; Shawn E Levy; R Stokes Peebles; Theresa T Pizarro; James R Goldenring Journal: Gut Date: 2017-02-14 Impact factor: 23.059
Authors: Nina Bertaux-Skeirik; Mark Wunderlich; Emma Teal; Jayati Chakrabarti; Jacek Biesiada; Maxime Mahe; Nambirajan Sundaram; Joel Gabre; Jennifer Hawkins; Gao Jian; Amy C Engevik; Li Yang; Jiang Wang; James R Goldenring; Joseph E Qualls; Mario Medvedovic; Michael A Helmrath; Tayyab Diwan; James C Mulloy; Yana Zavros Journal: J Pathol Date: 2017-08 Impact factor: 7.996
Authors: Victoria G Weis; Christine P Petersen; Jared A Weis; Anne R Meyer; Eunyoung Choi; Jason C Mills; James R Goldenring Journal: Am J Physiol Gastrointest Liver Physiol Date: 2016-11-23 Impact factor: 4.052
Authors: Takahiro Shimizu; Eunyoung Choi; Christine P Petersen; Jennifer M Noto; Judith Romero-Gallo; Maria B Piazuelo; M Kay Washington; Richard M Peek; James R Goldenring Journal: J Pathol Date: 2016-06-22 Impact factor: 7.996