Macrophages Promote Progression of Spasmolytic Polypeptide-Expressing Metaplasia After Acute Loss of Parietal Cells
Macrophages Promote Progression of Spasmolytic Polypeptide-Expressing Metaplasia After Acute Loss of Parietal Cells
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DOI：
10.1053/j.gastro.2014.02.007
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发表时间：
2014-06-01
期刊：
影响因子：
29.4
通讯作者：
Goldenring, James R.
中科院分区：
文献类型：
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作者：
Petersen, Christine P.;Weis, Victoria G.;Goldenring, James R.
背景与目的：壁细胞的丧失通过主细胞的转分化引起痉挛性多肽表达化生（SPEM）的发展。在存在炎症的情况下，SPEM可以发展成更具增殖性的化生，并增加了精氨酸特异性转录物的表达。我们用L 635诱导小鼠急性SPEM伴炎症，并研究炎症细胞在SPEM发生中的作用。方法：为了研究获得性免疫系统，Rag 1基因敲除、干扰素g缺陷和野生型（对照）小鼠接受L 635 3天。为了研究先天免疫系统，在L 635给药前2天和整个给药过程中，通过腹膜内注射氯膦酸盐脂质体消耗巨噬细胞。在L 635给药前2天和整个给药过程中，通过腹膜内注射抗Ly 6 G的抗体消耗中性粒细胞。病理学和免疫组化分析用于确定消耗效率、化生和增殖。为了表征每个模型中的SPEM，收集胃组织并测量Cftr、Dmbt 1和Gpx 2 mRNA的水平。巨噬细胞极化的标志物被用于识别招募到胃粘膜的巨噬细胞亚群。研究结果：给予L 635 Rag 1基因敲除、干扰素-γ-缺陷和嗜中性粒细胞-耗尽的小鼠导致增殖性SPEM的发展和SPEM细胞中丝氨酸特异性转录物的上调，与对照组相似。然而，与给予L 635的对照小鼠相比，给予L 635的巨噬细胞耗竭小鼠的SPEM细胞数量、SPEM细胞增殖和精氨酸特异性转录物的表达显著减少。在给予L 635的小鼠以及肠上皮化生患者中，M2巨噬细胞是主要的炎症成分。结论：小鼠模型和人类化生组织的研究结果表明，M2巨噬细胞在炎症存在的情况下促进SPEM的进展。
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-g-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-gamma-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.