Effects of apoptotic epithelial cell engulfment on mucosal inflammation

描述（由申请方提供）：上皮将大量管腔抗原与底层胃肠道组织分离，在该位置，它是遇到许多病原体的第一个部位。上皮细胞从腺体深层的干细胞中产生，当它们向管腔迁移时分化。到达腺体或绒毛的顶部后，上皮细胞死亡并斯劳进入管腔或被固有层内的吞噬细胞吞噬。抗原提呈细胞（APC）包括巨噬细胞和树突状细胞，可通过吞噬或自噬作用清除细菌、细胞碎片和死细胞。吞噬凋亡细胞通常是抗炎的，因为它刺激TGF-β的释放。适当的吞噬作用在控制胃肠炎症中的重要性得到了凋亡细胞受体缺陷的小鼠发展结肠炎的事实的支持。相比之下，当细胞携带肠道沙门氏菌血清型鼠伤寒沙门氏菌的细胞内感染时经历细胞凋亡的细胞可能充当微生物“特洛伊木马”，其将内化的细菌转运到APC中，从而刺激炎症反应。因此，我推测凋亡上皮细胞被抗原呈递细胞识别和吞噬，这一过程调节了局部炎症反应。具体来说，我建议确定是否吞噬人类上皮细胞凋亡的细胞内感染的情况下，积极抗炎，而感染的尸体吸收有利于诱导炎症。该提案的目的是定义控制整个人类胃肠道中凋亡细胞识别和吞噬的分子基础以及该过程对免疫调节的影响。这些目标将在以下具体目标中实现：目标1：定义哪些结构识别肠道中的凋亡上皮细胞。目的2：检测调节上皮细胞尸体吞噬的信号事件。目的3：研究细菌蛋白在调节Rac 1激活和粘膜炎症中的作用。虽然先天免疫的许多方面已被研究，很少有人知道的机制，细胞凋亡，上皮细胞吞噬在人体消化道和当地的主机响应的影响。我们知识上的这一差距使得所提出的研究成为一个令人兴奋的新前沿，与人类粘膜免疫具有广泛的相关性。本研究将探讨吞噬细胞介导凋亡上皮细胞吞噬的机制，以及这一过程如何影响粘膜炎症。建立一个新的作用，吞噬和受体参与这一过程将导致未来的翻译研究，模拟这一过程在人类消化道。这一新的信息可能具有预防或治疗感染引发的消化系统疾病的治疗应用，包括炎症性肠病和感染性腹泻。

DESCRIPTION (provided by applicant): The epithelium separates the vast array of luminal antigens from the underlying gastrointestinal tissue and in this position, it serves as the first site to encounter many pathogens. Epithelial cells emerge from stem cells from the deeper layers of the glands which differentiate as they migrate towards the lumen. After reaching the top of the gland or villous, 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-¿. 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. In contrast, cells that undergo apoptosis when they carry an intracellular infection with Salmonella enterica serovar Typhimurium may act as a microbial "Trojan horse" that transports internalized bacteria into the APC thereby stimulating inflammatory responses. Thus, I hypothesize that apoptotic epithelial cells are recognized and engulfed by antigen presenting cells and this process modulates local inflammatory responses. Specifically, I propose to determine if engulfment of human epithelial cells rendered apoptotic in the absence of intracellular infections are actively anti-inflammatory while uptake of infected corpses favors the induction of inflammation. The objective of this proposal is to define the molecular basis governing the recognition and engulfment of apoptotic cells throughout the human gastrointestinal tract and the impact of this process on immune regulation. These objectives will be achieved in the following Specific Aims: Aim 1: Define which structures recognize apoptotic epithelial cells in the gut. Aim 2: Examine the signaling events that regulate the engulfment of epithelial cell corpses. Aim 3: Examine the role of bacterial proteins in regulating Rac1 activation and mucosal inflammation. 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. This proposal will examine the mechanisms by which phagocytes mediate the engulfment of apoptotic epithelial cells and how this process impacts mucosal inflammation. Establishing a novel role for engulfment and the receptors involved in this process will lead to future translational studies that model this process in the human digestive tract. This new information may have therapeutic applications for the prevention or treatment of digestive diseases triggered by infection including inflammatory bowel diseases and infectious diarrhea.