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Impairment of a NIK-SIX Feedback Axis Results in Dysregulation of Intestinal Immune Homeostasis and Promotes Early-onset Fatal Spontaneous Colitis | ||
| Iranian Journal of Immunology | ||
| دوره 19، شماره 3، آذر 2022، صفحه 263-277 اصل مقاله (2.18 M) | ||
| نوع مقاله: Original Article | ||
| شناسه دیجیتال (DOI): 10.22034/iji.2022.90031.1985 | ||
| نویسندگان | ||
| Yu Xia Zhao1؛ Hong Mei1؛ Yang Xin Huang2؛ Jia Qing Chen* 3 | ||
| 1Department of Gastroenterology, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China | ||
| 2Department of Epidemiology and Biostatistics, College of Public Health, University of South Florida, Florida, USA | ||
| 3Department of Statistics, School of Science, Wuhan University of Technology, Wuhan, China | ||
| چکیده | ||
| Background: The negative feedback circuit NIK-SIN could inhibit the systemic inflammation and protect mouse from endotoxic shock. However, the physiological significance of NIK-SIX feedback circuit in the maintenance of intestinal immune homeostasis and prevention of early-onset spontaneous colitis is not known. Objective: To explore the role of NIK-SIX axis in the maintenance of intestinal immune homeostasis. Methods: The conditional knockout of NIK encoding gene, Map3k14, in the Cd11c+ dendritic cells were generated by crossing Map3k14-flox mice with Cd11c-Cre mice. DSS was used for colitis models. The expression of cytokines in the intestinal immune cells, isolated from Map3k14-cKO mice were detected by qPCR. The siRNA molecules were used for the silencing of SIN-proteins. Then luciferase assays and chromatin immunoprecipitation combined with qPCR were applied for mechanism investigations. Results: The expression of SIX1 and SIX2 protein in BMDMs from WT were significantly lower than in the Map3k14-cKO mice. In vitro, the NIK-/- human-derived circulating monocytes also failed to express SIX-proteins under the stimulation of non-canonical NF-κB agonists. The expression of cytokines was significantly decreased in human circulating monocytes with overexpression SIN-proteins. The expression of cytokines in macrophages, DCs and T cells isolated from Map3k14-cKO mice were significantly increased in the DSS-induced models. Higher expression of cytokines was observed in the SIN1-/- and SIN2-/- cells including human circulating monocytes, mouse-derived BMDMs, intestinal macrophages and DCs. SIN-proteins directly bound the promoter region of inflammatory genes. Conclusion: NIK-SIX axis down-regulated inflammatory gene expression and plays a pivotal role in the maintenance of intestinal immune homeostasis. | ||
| کلیدواژه‌ها | ||
| Intestinal Immune Homeostasis؛ NF-κB Inducing Kinase؛ SIX؛ Spontaneous Colitis | ||
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