Colonic gene expression profile in NHE3-deficient mice: evidence for spontaneous distal colitis
Colonic gene expression profile in NHE3-deficient mice: evidence for spontaneous distal colitis
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DOI：
10.1152/ajpgi.90207.2008
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发表时间：
2008-07-01
影响因子：
4.5
通讯作者：
Ghishan, Fayez K.
中科院分区：
文献类型：
--
作者：
Laubitz, Daniel;Larmonier, Claire B.;Ghishan, Fayez K.
Na+/ H+交换器3（NHE 3）是小肠Na+吸收的主要途径。NHE 3被认为是促炎细胞因子和肠道致病菌的靶点，受损的NHE 3表达和/或活性可能是炎症相关性腹泻的原因。然而，NHE 3功能丧失是否会影响肠道免疫稳态尚未研究。在这份报告中，我们描述了NHE 3缺陷小鼠自发发展局限于远端结肠粘膜的结肠炎。在常规设施中饲养的NHE 3（-/-）小鼠表现出表型特征，如轻度腹泻、偶尔直肠脱垂和体重减轻。全基因组微阵列分析不仅发现了大量可能代表适应性反应的转运基因，而且还发现了大量与炎症反应一致的基因。组织学检查证实远端结肠的变化与活动性炎症一致，包括隐窝增生伴5-溴-2 '-脱氧尿苷阳性细胞数量增加、弥漫性嗜酸性浸润伴基质金属蛋白酶8表达增加15倍、pSer（276）-RelA阳性细胞数量增加和高碘酸-希夫阳性杯状细胞显著减少。实时PCR显示NHE 3（-/-）小鼠远端结肠中诱导型一氧化氮合酶（38倍）、TNF-α（6倍）、巨噬细胞炎症蛋白-2（48倍）和IL-18（3倍）的表达升高。NHE 3（-/-）小鼠在远端结肠中显示出增强的细菌粘附和移位。口服广谱抗生素可改善结肠炎.总之，NHE 3缺乏导致先天性免疫反应加剧，这一观察结果表明NHE 3作为修饰基因的潜在新作用，当在感染性或慢性结肠炎期间下调时，可以调节结肠炎症的程度和严重程度。
Na+/ H+ exchanger 3 (NHE3) provides a major route for intestinal Na+ absorption. NHE3 has been considered a target of proinflammatory cytokines and enteropathogenic bacteria, and impaired NHE3 expression and/or activity may be responsible for inflammationassociated diarrhea. However, the possibility of loss of NHE3 function reciprocally affecting gut immune homeostasis has not been investigated. In this report, we describe that NHE3-deficient mice spontaneously develop colitis restricted to distal colonic mucosa. NHE3 (-/-) mice housed in a conventional facility exhibited phenotypic features such as mild diarrhea, occasional rectal prolapse, and reduced body weight. Genomewide microarray analysis identified not only a large group of transport genes that potentially represent an adaptive response, but also a considerable number of genes consistent with an inflammatory response. Histological examination demonstrated changes in the distal colon consistent with active inflammation, including crypt hyperplasia with an increased number of 5-bromo- 2 '-deoxyuridine- positive cells, diffuse neutrophilic infiltrate with concomitant 15-fold increase in matrix metalloproteinase 8 expression, an increased number of pSer(276)-RelA-positive cells, and a significant decrease in periodic acid-Schiff-positive goblet cells. Real-time PCR demonstrated elevated expression of inducible nitric oxide synthase ( 38-fold), TNF- alpha (6-fold), macrophage inflammatory protein-2 ( 48-fold), and IL-18 (3-fold) in the distal colon of NHE3 (-/-) mice. NHE3 (-/-) mice showed enhanced bacterial adhesion and translocation in the distal colon. Colitis was ameliorated by oral administration of broad- spectrum antibiotics. In conclusion, NHE3 deficiency leads to an exacerbated innate immune response, an observation suggesting a potentially novel role of NHE3 as a modifier gene, which when downregulated during infectious or chronic colitis may modulate the extent and severity of colonic inflammation.