Department of Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, CA, United States.
Department of Nutrition, University of California, Davis, Davis, CA, United States.
Front Immunol. 2022 Aug 22;13:894649. doi: 10.3389/fimmu.2022.894649. eCollection 2022.
Intelectins are carbohydrate-binding proteins implicated in innate immunity and highly conserved across chordate evolution, including both ascidians and humans. Human intelectin-1 (ITLN1) is highly abundant within the intestinal mucosa and binds microbial but not host glycans. Genome-wide association studies identified SNPs in that are linked to susceptibility for Crohn's disease. Moreover, ITLN1 has been implicated in the pathophysiology of obesity and associated metabolic disease. To gain insight on biological activities of human ITLN1 , we developed a C57BL/6 mouse model genetically targeting the gene encoding the functional mouse ortholog. In wild-type C57BL/6 mice, both mRNA and protein analysis showed high expression of in the small intestine, but manifold lower levels in colon and other extraintestinal tissues. Whereas intestinal expression of human ITLN1 localizes to goblet cells, our data confirm that mouse Itln1 is expressed in Paneth cells. Compared to wild-type littermate controls, mice homozygous for the hypomorphic trapping allele had reduced expression levels of expression (~10,000-fold). The knockout mice exhibited increased susceptibility in an acute model of experimentally induced colitis with 2% w/v dextran sulfate sodium (DSS). In a model of chronic colitis using a lower dose of DSS (1.5% w/v), which enabled a detailed view of disease activity across a protracted period, no differences were observed in body weight, fecal texture, hemoccult scores, food/water intake, or colon length at necropsy, but there was a statistically significant genotype over time effect for the combined fecal scores of disease activity. In model of diet-induced obesity, using two western-style diets, which varied in amounts of sugar (as sucrose) and saturated fat (as lard), mice with expression ablated showed no increased susceptibility, in terms of weight gain, food intake, plasma markers of obesity compared to wildtype littermates. While the mouse genetic knockout model for holds promise for elucidating physiological function(s) for mammalian intelectins, results reported here suggest that Itln1, a Paneth cell product in C57BL/6 mice, likely plays a minor role in the pathophysiology of chemically induced colitis or diet-induced obesity.
凝集素是参与先天免疫的糖结合蛋白，在脊索动物进化过程中高度保守，包括尾索动物和人类。人类凝集素-1（ITLN1）在肠道黏膜中含量丰富，可结合微生物而不是宿主糖。全基因组关联研究发现与克罗恩病易感性相关的 中的 SNP。此外，ITLN1 与肥胖症和相关代谢性疾病的病理生理学有关。为了深入了解人类 ITLN1 的生物学活性，我们构建了一种靶向编码功能鼠同源物的基因的 C57BL/6 小鼠模型。在野生型 C57BL/6 小鼠中，mRNA 和蛋白质分析均显示 在小肠中高表达，但在结肠和其他肠外组织中低表达几倍。虽然人 ITLN1 的肠道表达定位于杯状细胞，但我们的数据证实鼠 Itln1 在潘氏细胞中表达。与野生型同窝对照相比，携带 隐性捕获等位基因的纯合子小鼠的 表达水平降低（~10,000 倍）。敲除小鼠在 2%w/v 葡聚糖硫酸钠（DSS）的实验性诱导结肠炎急性模型中易感性增加。在使用较低剂量 DSS（1.5%w/v）的慢性结肠炎模型中，由于能够在较长时间内详细观察疾病活动，在尸检时体重、粪便质地、潜血评分、食物/水摄入或结肠长度没有差异，但在粪便评分的综合疾病活动方面，基因型随时间的变化有统计学意义。在饮食诱导肥胖模型中，使用两种西式饮食，糖（蔗糖）和饱和脂肪（猪油）的含量不同，与野生型同窝对照相比， 表达缺失的小鼠在体重增加、食物摄入、肥胖的血浆标志物方面没有增加易感性。虽然 的小鼠基因敲除模型有望阐明哺乳动物凝集素的生理功能，但这里报道的结果表明，C57BL/6 小鼠的 Paneth 细胞产物 Itln1 可能在化学诱导性结肠炎或饮食诱导性肥胖的病理生理学中发挥次要作用。
