Goblet Cell Secretion and Antigen Delivery

杯状细胞分泌和抗原递送

• 批准号: 8734902
• 负责人: Kathryn A Knoop
• 金额: $ 5.51万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-05 至 2015-10-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8734902
• 关键词: Acetylcholine; Address; Adult; Aftercare; Antibiotics; Antigens; Bacteria; Calcium; Carbamoylcholine; Cell Culture Techniques; Cell secretion; Cells; Colon; Crohn' s disease; Dendritic Cells; Diet; Digestive System Disorders; Enteral; Epithelial; Epithelial Cells; Epithelium; Exocytosis; Germ-Free; Goblet Cells; Grant; Growth; Growth Factor Receptors; Health; Homeostasis; House mice; Housing; Immune response; Immune system; In Vitro; Infection; Inflammatory Response; Intestines; Lamina Propria; Ligands; Mediating; Microscopy; Mitogen-Activated Protein Kinases; Modeling; Mus; Muscarinic Acetylcholine Receptor; Neonatal; Pathway interactions; Phosphorylation; Receptor Activation; Receptor Signaling; Regulation; Role; Salmonella typhimurium; Sampling; Signal Transduction; Small Intestinal Goblet Cell; Small Intestines; Specific Pathogen Frees; Stimulus; Testing; Tissues; Transactivation; Ulcerative Colitis; Villous; acetylcholine receptor agonist; base; germ free condition; in vivo; inhibitor/antagonist; intestinal epithelium; intestinal homeostasis; microbial; neonate; prevent; public health relevance; receptor expression; research study; response; sensor; two-photon

DESCRIPTION (provided by applicant): The intestinal epithelium is a dynamic barrier that protects the body from the multitudes of bacteria that reside in the lumen. Yet multiple mechanisms exist allowing sampling of the lumen in order to promote tolerance and prevent inflammatory responses against innocuous dietary antigens. Through the use of two-photon (2p) microscopy, goblet cells (GC) were recently identified as a delivery mechanism for soluble antigen to the CD103+ dendritic cells residing in the villous lamina propria suggesting this mechanism promotes a tolerogenic immune response. We refer to these antigen delivery cells as Goblet Cell Associated Antigen Passages (GAPs). The formation of GAPs appears to be connected to the release of GC products during calcium- mediated compound exocytosis (CE), in response to acetylcholine through muscarinic receptors (mAchR). At steady-state, CE and GAP formation only occurs in the small intestine but not the colon of specific pathogen free-housed adult mice (SPF). However we did observe GAPs in the colon of germfree mice, neonatal SPF-housed mice, and Myd88-/- mice with altered microbial signaling. In this proposal, we hypothesize GAP formation and CE occurs through stimulation of the mAchR on GCs, and that this pathway is inhibited by TLR and NOD signaling in response to increased microbial growth or pathogenic infections. We propose to elucidate the details of how mAchR signaling leads to CE and where TLR and NOD intersect the signaling cascade. Through this grant, we hope to better understand how GAPs deliver antigen for the purpose of maintaining tolerogenic immune responses.

描述（由申请人提供）：肠上皮是一个动态屏障，可以保护身体免受肠腔内大量细菌的侵害。然而，存在多种机制允许对管腔进行采样，以促进耐受性并防止针对无害饮食抗原的炎症反应。通过使用双光子 (2p) 显微镜，最近发现杯状细胞 (GC) 是一种将可溶性抗原递送至位于绒毛固有层中的 CD103+ 树突状细胞的机制，表明该机制可促进耐受性免疫反应。我们将这些抗原递送细胞称为杯状细胞相关抗原通道（GAP）。 GAP 的形成似乎与钙介导的化合物胞吐作用 (CE) 期间 GC 产物的释放有关，通过毒蕈碱受体 (mAchR) 响应乙酰胆碱。在稳态下，CE 和 GAP 的形成仅发生在特定病原体自由饲养的成年小鼠 (SPF) 的小肠中，而不是结肠中。然而，我们确实在无菌小鼠、新生 SPF 饲养小鼠和 Myd88-/- 小鼠的结肠中观察到了微生物信号改变的 GAP。在这个提议中，我们假设 GAP 形成和 CE 通过刺激 GC 上的 mAchR 发生，并且该通路被 TLR 和 NOD 信号传导抑制，以响应微生物生长或病原体感染的增加。我们建议阐明 mAchR 信号传导如何导致 CE 以及 TLR 和 NOD 与信号级联相交的细节。通过这笔资助，我们希望更好地了解 GAP 如何传递抗原以维持耐受性免疫反应。