Rethinking the "quiet" nature of apoptotic cell clearance.

项目摘要 每天都有数十亿细胞死亡，并迅速清除，免疫后果最小。这个过程， 凋亡细胞或巨噬细胞的清除是由吞噬细胞如巨噬细胞进行的， 在组织中的数量较少，并且通常负责清除快速坏死的多个死细胞和碎片。 传承为胞饮作用被认为对于预防自身免疫和炎性疾病是重要的。 然而，患有自身免疫性或炎症性疾病的患者很少出现预期的症状， 凋亡细胞清除缺陷，如凋亡或坏死细胞的过度积累。对 一方面，每个组织和器官都有一个过程，但另一方面，它仍然存在， 尚不清楚这一过程如何促进或预防自身免疫和炎症性疾病。我们提出了一种新 一个模型表明，自身免疫和炎症性疾病的出现是因为巨噬细胞如何 管理凋亡细胞的消化，而不是巨噬细胞是否吞噬。该模型表明， 细胞凋亡是一个危险的过程，因为吞噬的凋亡细胞的内容物，如脂质，氨基酸， 和核酸，可以通过巨噬细胞引发潜在的灾难性炎症反应。为了防止这种情况， 我们假设巨噬细胞使用机制来快速检测和响应被吞噬的物质， 快速响应电路（RRC）。该建议结合了新颖的实验与组学方法 和信息学来识别和组装假定的红细胞增多症RRC，然后使用创新的工具和方法， 以机械地研究鉴定的红细胞增多症RRC。使用这种方法，我们将首先检查常见的 巨噬细胞使用的红细胞增多症RRC。然后，我们将探索组织使用的独特的红细胞增多症RRC- 驻留巨噬细胞，其暴露于对驻留组织特异性的垂死细胞和碎片。总的来说， 这项关于RRC的工作将有助于建立一个新的框架，以了解如何正确地消化 凋亡细胞有助于自身免疫和炎性疾病，并可能揭示新的诊断方法， 治疗学

PROJECT SUMMARY Each day billions of cells die and are cleared rapidly with minimal immunological consequence. This process, clearance of apoptotic cells or efferocytosis, is carried out by phagocytes such as macrophages which are numerically fewer in tissues and are often responsible for clearing multiple dead cells and debris in quick succession. Efferocytosis is thought to be important for preventing autoimmunity and inflammatory disease. However, patients suffering from autoimmunity or inflammatory disease rarely present with symptoms expected from a defect in clearance of apoptotic cells, such as excessive accumulation of apoptotic or necrotic cells. On one hand, you have a process that is occurring in every tissue and organ, yet on the other hand, it remains unclear how this process contributes to or prevents autoimmunity and inflammatory disease. We present a new model that suggests autoimmunity and inflammatory disease arise because of disruptions in how macrophages manage apoptotic cell digestion instead of whether or not macrophages engulf at all. This model suggests that efferocytosis is a dangerous process because the content of engulfed apoptotic cells, such as lipids, amino acids, and nucleic acids, can trigger potentially catastrophic inflammatory responses by macrophages. To prevent this, we hypothesize that macrophages use mechanisms to rapidly detect and respond to the engulfed material, termed rapid response circuits (RRCs). This proposal combines novel experimentation with -omics approaches and informatics to identify and assemble putative efferocytosis RRCs, then uses innovative tools and methods to mechanistically study identified efferocytosis RRCs. Using this approach, we will first examine the common efferocytosis RRCs used by macrophages. Then, we will explore unique efferocytosis RRCs used by tissue- resident macrophages who are exposed to dying cells and debris specific to the tissue of residence. Collectively, this work on RRCs will contribute to a new framework for understanding how failure to appropriately digest apoptotic cells contributes to autoimmunity and inflammatory disease, and possibly reveal novel diagnostics and therapeutics.