Mechanisms of apoptotic cell clearance in the human stomach

描述（由申请人提供）：上皮将大量腔内抗原从胃肠道组织和该部位分离；它是遇到许多病原体的第一个地点。胃上皮细胞来自于腺体深层的干细胞，当它们向管腔迁移时分化。上皮细胞到达中央凹窝顶部后死亡，要么进入管腔，要么被固有层内的吞噬细胞吞没。包括巨噬细胞和树突状细胞在内的抗原呈递细胞（APC）可以通过吞噬或自噬来清除细菌、细胞碎片和死细胞。凋亡细胞的吞噬通常是抗炎的，因为它刺激TGF-b的释放。缺乏凋亡细胞受体的小鼠可发生结肠炎，这一事实支持了适当吞噬在控制胃肠道炎症中的重要性。然而，没有人研究过在幽门螺杆菌感染期间，当上皮细胞凋亡增加时，正常或炎症胃组织吞噬的结果。从人胃肠道粘膜分离的巨噬细胞反应低下。然而，在慢性炎症期间，胃肠道APC细胞失去这种低反应性并促进炎症。正在验证的假设是，凋亡的胃上皮细胞被抗原提呈细胞识别和吞噬，这一过程调节局部炎症反应。具体来说，我将确定结果是否人类上皮细胞吞噬调节与幽门螺杆菌感染相关的炎症。本应用程序的目的是确定人类胃中凋亡细胞识别和吞噬的分子基础，并评估这一过程对健康和疾病免疫调节的影响。这将在以下特定目的中进行检查：目的1：评估有助于凋亡上皮细胞内化的受体。目的2：定义调节上皮细胞尸体吞噬的下游反应。目的3：研究吞噬调节胃炎症的分子基础。目的4：确定吞噬分子在人胃中的表达和功能。虽然先天免疫的许多方面已经被研究过，但对人类消化道中凋亡、上皮细胞吞噬的机制及其对局部宿主反应的影响知之甚少。这一知识上的差距使我们提出的研究成为一个令人兴奋的新前沿，与人类粘膜免疫特别是胃免疫生物学有着广泛的相关性。

DESCRIPTION (provided by applicant): The epithelium separates the vast array of luminal antigens from the underlying gastrointestinal tissue and from this position; it serves as the first site to encounter many pathogens. Gastric epithelial cells emerge from stem cells within the deeper regions of the glands that differentiate as they migrate towards the lumen. After reaching the top of the foveolar pits, epithelial cells die and either slough into the lumen or get engulfed by phagocytes within the lamina propria. Antigen presenting cells (APC) including macrophages and dendritic cells can remove bacteria, cellular debris and dead cells through phagocytosis or autophagy. Engulfment of apoptotic cells is generally anti- inflammatory since it stimulates the release of TGF-b. The importance of proper phagocytosis in the control of gastrointestinal inflammation is supported by the fact that mice deficient in a receptor for apoptotic cells develop colitis. However, nobody has ever studied the outcome of engulfment in normal or inflamed gastric tissue during H. pylori infection when epithelial cell apoptosis is increased. Macrophages isolated from human gastrointestinal mucosa are hyporesponsive. However, during chronic inflammation, gastrointestinal APC cells lose this hyporesponsiveness and contribute to the inflammation. The hypothesis being tested is that apoptotic gastric epithelial cells are recognized and engulfed by antigen presenting cells and this process modulates local inflammatory responses. Specifically, I will determine if the outcome human epithelial cell engulfment modulates inflammation associated with H. pylori infection. The objective of this application is to define the molecular basis for the recognition and engulfment of apoptotic cells in the human stomach and to assess the impact of this process on immune regulation in health and disease. This will be examined in the following Specific Aims: Aim 1: Evaluate the receptors contributing to the internalization of apoptotic epithelial cells. Aim 2: Define the downstream responses that regulate the engulfment of epithelial cell corpses. Aim 3: Examine the molecular basis by which engulfment regulates gastric inflammation. Aim 4: Determine the expression and function of engulfment molecules in the human stomach. Although many aspects of innate immunity have been studied, little is known about the mechanisms of apoptotic, epithelial cell engulfment in the human digestive tract and their impact on local host responses. This gap in our knowledge makes the proposed studies an exciting new frontier with broad relevance for mucosal immunity in humans and gastric immunobiology in particular. PUBLIC HEALTH RELEVANCE: This application will examine the mechanisms whereby phagocytes internalize apoptotic gastric epithelial cells and how the engulfment of apoptotic epithelial cells impacts gastritis. These studies also provide a translational component that will investigate this process directly in the human stomach. This new information may have broader therapeutic applications for the prevention or treatment of digestive diseases triggered by infection including gastritis, inflammatory bowel diseases and infectious diarrhea.