Mechanisms regulating apoptotic cell clearance in health and disease

摘要 令人惊叹的是，我们的身体在生命的每一秒都会翻转/循环大约一百万个细胞(0.1%- 每日体重的0.4%)。翻转的像元可以包括作为正常的一部分生成的多余像元 发育、动态平衡、用过/老化的细胞，以及因疾病或感染而受损的细胞。虽然 细胞死亡有多种形式，其中绝大多数细胞是通过细胞凋亡而死亡的。专业吞噬细胞 (如巨噬细胞和未成熟树突状细胞)或邻近细胞(成纤维细胞和上皮细胞)，如 以及特殊的吞噬细胞(如支持细胞)介导死亡细胞的清除。提示符和 有效地清除细胞在几个层面上都很重要，包括为生活替代创造空间 细胞，预防炎症，维持组织/器官的功能，进而，健康的 有机体立方米。当凋亡细胞不能及时清除时，可能会导致继发性坏死和 从未清除的细胞中释放它们的细胞内内容物，并倾向于自身免疫， 动脉粥样硬化和某些神经病理。此外，常见的凋亡细胞是如何 活跃的肿瘤生长和化疗、放射或免疫治疗后与 对肿瘤来源细胞的免疫抑制或免疫反应。而凋亡细胞领域 清除是令人兴奋的，到目前为止的研究已经确定了一些基本步骤，仍然有大量和 我们的知识中存在着巨大的差距。其中一些包括：为什么我们身上有这么多吞噬受体 吞噬细胞，有没有通过这些受体的独特信号，我们有可能提高吞噬能力吗？ 在特定的疾病条件下抑制炎症，吞噬细胞(如巨噬细胞)如何 摄取如此多的“货物”，并仍然维持其正常的代谢组学等，而这些都是大的 这些问题本身也是相互关联的，在过去的15年里，我们的实验室获得了和 使用了不同的工具来解决这些问题，我们也为推动这一领域做出了重大贡献 在几个激动人心的方向上。这个Mira项目的总体目标是采用新的方法，这将有助于 我们更好地定义了凋亡细胞清除过程的关键步骤/分子特征，并试图 在疾病模型中调节吞噬机制以获得可能的治疗效果。

Abstract It is truly remarkable that our bodies turn over/recycle about one million cells every second of life (0.1%- 0.4% of body mass daily). The cells that are turned over can include excess cells generated as part of normal development, homeostasis, used/aged cells, and damaged cells that arise from disease or infections. Although there are many forms of cell death, a large majority of these cells die via apoptosis. Professional phagocytes (such as macrophages and immature dendritic cells), or neighboring cells (fibroblasts and epithelial cells), as well as specialized phagocytes (such as Sertoli cells) mediate the removal of the dying cells. The prompt and efficient removal of cells is important at several levels, including `making space' for replacement by living cells, preventing inflammation, maintaining the function of the tissue/organ, and in turn, a healthy organism3. When apoptotic cells fail to be cleared promptly, this can lead to secondary necrosis and the release of their intracellular contents from uncleared cells, and a predilection to autoimmunity, atherosclerosis, and certain neurological pathologies. Moreover, how apoptotic cells that are often seen in actively growing tumors and after chemo-, radiation-, or immuno-therapies has relevance to immunosuppression or immune responses to the tumor derived cells. While the field of apoptotic cell clearance is exciting ,and studies to date have identified some of the basic steps, there are still large and significant gaps in our knowledge. Some of these include: why do we have so many engulfment receptors on phagocytes, are there unique signals via these receptors, can we possibly dial up the capacity for engulfment to dampen inflammation in specific disease conditions, and how does a phagocyte (such as a macrophage) take up so much excess `cargo' and still maintain its normal metabolomics, etc. While these are large questions unto itself, these are also inter-related, and over the past 15 years, our laboratory has obtained and used different tools to address these questions, and we have also significantly contributed to moving this field in several exciting directions. The overall goal of this MIRA project is to take novel approaches that will help us better define the key steps/molecular features of the apoptotic cell clearance process and also attempt to modulate the engulfment machinery for possible therapeutic benefits in disease models.