The spatiotemporal development of mesenteric lymphatic changes in the TNFΔARE/+ mouse model of terminal ileitis.

IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Keith Keane, Matthew Stephens, Simon Roizes, Jingna Xue, Shan Liao, Pierre-Yves von der Weid
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引用次数: 0

Abstract

Crohn's disease (CD) is a chronic inflammatory bowel disease, which also encompasses significant alterations of the mesenteric lymphatic system. Whether these changes are a mere consequence of or directly contribute to the inflammation is unknown. Here, we characterized the spatial and temporal development of these events in the TNFΔARE/+ mouse, which develops CD-like ileitis and significant mesenteric lymphatic alterations. At 8, 12, 20, and 28 wk of age, specific pathogen-free (SPF), germ-free (GF) TNFΔARE/+ and wild-type (WT) mice were assessed for ileitis via myeloperoxidase (MPO) activity while mesenteric lymphatic alterations were assessed by confocal immunofluorescence imaging. Lymphatic alterations in the SPF TNFΔARE/+ occurred in a stepwise manner between 8 and 28 wk of age beginning with the development of mesenteric lymphadenopathy at 8 wk despite no significant ileitis. By 12-wk ileal MPO significantly elevates concomitantly with lymphangiectasia of the mesenteric collecting lymphatic vessels (CLVs) and clustering of CD45+ immune cells around them. At 20 wk, significant lymphangiogenesis of the initials (initial lymphatic vessel) and tertiary lymphoid organs aligned along lymphatic collectors (CA-TLOs) had developed. At 28 wk, lymphangiectasia, lymphangiogenesis, and CA-TLOs increased. However, 28-wk-old GF TNFΔARE/+, while displaying no ileitis, presented with mesenteric lymphadenopathy, lymphangiectasia, and lymphangiogenesis but no immune cell clustering nor CA-TLOs. The TNFΔARE/+ mice develop terminal ileitis and lymphatic alterations in a stepwise manner beginning with mesenteric lymph node lymphadenopathy and ileal inflammation, followed by CLV dilation and lymphangiogenesis. These lymphatic alterations are exacerbated by the gut microbiome, with immune cell clustering and tertiary lymphoid organ formation being entirely dependent of its presence.NEW & NOTEWORTHY The mesenteric lymphatic system displays striking morphological alterations in Crohn's disease. To assess the importance of these changes in the perpetuation of the disease, we established the timeframe of their occurrence with respect to the development of ileitis in a mouse model of Crohn's disease and in the same model derived germ-free where intestinal inflammation does not occur. Although immune-related alterations seem to depend on microbiome, changes specifically affecting lymphatic vessels persist in its absence.

末梢回肠炎TNFΔARE/+小鼠模型肠系膜淋巴改变的时空发展。
克罗恩病(CD)是一种慢性炎症性肠病,也包括肠系膜淋巴系统的显著改变。这些变化是否仅仅是炎症的结果,还是直接导致炎症尚不清楚。在这里,我们描述了TNFΔARE/+小鼠中这些事件的时空发展,这些事件发展为cd样回肠炎和显著的肠系膜淋巴改变。在8、12、20和28周龄时,通过脊髓过氧化酶活性(MPO)评估特异性无病原体(SPF)、无细菌(GF) TNFΔARE/+和WT小鼠的回肠炎,同时通过共聚焦免疫荧光成像评估肠系膜淋巴改变。SPF TNFΔARE/+的淋巴改变在8周龄至28周龄之间逐步发生,尽管没有明显的回肠炎,但在8周龄时开始出现肠系膜淋巴结病。到12周时,回肠MPO显著升高,同时伴有肠系膜集合淋巴管(CLV)的淋巴管扩张和周围CD45+免疫细胞的聚集。20周时,沿淋巴收集器(CA-TLOs)排列的首淋巴(ILV)和三级淋巴器官出现了明显的淋巴管生成。28周时,淋巴管扩张、淋巴管生成和CA-TLOs增加。然而,28周大的GF TNFΔARE/+,虽然没有显示回肠炎,但表现为肠系膜淋巴结病变、淋巴管扩张和淋巴管生成,但没有免疫细胞聚集和CA-TLOs。TNFΔARE/+小鼠以逐步的方式发展终末回肠炎和淋巴改变,从MLN淋巴结病变和回肠炎症开始,随后是CLV扩张和淋巴管生成。这些淋巴改变被肠道微生物群加剧,免疫细胞聚集和TLO的形成完全依赖于它的存在。
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来源期刊
CiteScore
9.40
自引率
2.20%
发文量
104
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Gastrointestinal and Liver Physiology publishes original articles pertaining to all aspects of research involving normal or abnormal function of the gastrointestinal tract, hepatobiliary system, and pancreas. Authors are encouraged to submit manuscripts dealing with growth and development, digestion, secretion, absorption, metabolism, and motility relative to these organs, as well as research reports dealing with immune and inflammatory processes and with neural, endocrine, and circulatory control mechanisms that affect these organs.
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