Phospholipid signaling from apoptotic cells

来自凋亡细胞的磷脂信号传导

• 批准号: 7142871
• 负责人: DONNA L BRATTON
• 金额: $ 38.14万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7142871
• 关键词: apoptosis; biological signal transduction; cell migration; eicosanoids; gene targeting; genetically modified animals; human subject; inflammation; laboratory mouse; mass spectrometry; phagocytosis; phosphatidylcholines; phosphatidylserines; phospholipids

Following inflammation, apoptosis of unnecessary and damaged cells is a fundamental process of tissue restoration and repair. Engulfment and recycling of apoptotic cells by either professional or non-professional phagocytes results in their removal before noxious intracellular contents are dispersed, and actively suppresses inflammation. Indeed, defects in engulfment are linked to autoimmunity and over-exuberant inflammation. Increasing evidence suggests that phospholipids (PLs) of apoptosing cells serve as important signals for the recruitment, recognition and non-phlogistic engulfment by phagocytes. Unlike most other mediators, PLs are immediately available, but either latent (e.g phosphatidylserine (GPSer) which must be externalized), or can be "economically" modified to effectively signal the cell's demise. PL modification by oxidants, almost always present in apoptosis, and/or by remodeling phospholipases (PLA2s) is hypothesized to generate signaling PLs. Using sensitive mass spectrometry techniques, leading candidates for the attraction of phagocytes are proposed to be released lyso-phosphatidylcholine (lyso-GPCho), platelet activating factor (PAF), and lyso-GPSer species as well. The near-universal appearance of GPSer species in the plasma membrane outer leaflet results from inactivation of an aminophospholipid translocase (APLT) and activated PL flip-flop, and while GPSer is required for recognition, it is insufficient to drive phagocyte engulfment. Species of GPSer have not been defined and there is evidence that modification by oxidants is critical to the process. Preliminary data shows that both sn-2 and sn-1 lyso-GPSer are produced during apoptosis. Mounting data support the hypothesis that lyso-PLs signal for calcium flux, and as such, are hypothesized to drive PL flip-flop and inhibit the APLT in apoptosing cells (determined by lipid movements investigated by flow cytometry). Little is known of the identities or mechanisms of elaboration, presentation or release of these PL signals for apoptotic cell recognition. Stepwise, it is hypothesized that ; i) oxidants and/or activation of PLA2s during apoptosis result in elaboration of signaling GPCho and GPSer species, ii) loss of APLT activity and activated PL flip-flop moves them across the plasma membrane in a manner that is, in part, driven by the PL species themselves, and iii) their release to the media, or retention on the surface of the apoptosing cell signals for phagocytic recruitment and non-phlogistic engulfment.

炎症后，不必要和受损细胞的凋亡是组织恢复和修复的基本过程。凋亡细胞被专职或非专职吞噬细胞吞噬和再循环导致它们在有害的细胞内内容物分散之前被去除，并积极抑制炎症。事实上，吞噬的缺陷与自身免疫和过度旺盛的炎症有关。越来越多的证据表明，吞噬细胞的磷脂（PL）是吞噬细胞募集、识别和非炎性吞噬的重要信号。与大多数其他调解人不同，PL是 在一些实施方案中，细胞可以立即获得，但要么是潜伏的（例如磷脂酰丝氨酸（GPSer），其必须被外化），要么可以被“经济地”修饰以有效地发出细胞死亡的信号。PL修饰氧化剂，几乎总是存在于细胞凋亡，和/或重塑磷脂酶（PLA 2）被假设产生信号PL。利用灵敏的质谱技术，提出了吸引吞噬细胞的主要候选物， 释放溶血磷脂酰胆碱（lyso-GPCho）、血小板活化因子（PAF）和溶血GPSer物质。质膜外小叶中GPSer种类的几乎普遍出现是由于氨基磷脂移位酶（APLT）的失活和激活的PL触发器，虽然GPSer是识别所必需的，但它不足以驱动吞噬细胞吞噬。GPSer的种类尚未确定，有证据表明氧化剂的修饰对该过程至关重要。初步数据显示，在细胞凋亡过程中产生sn-2和sn-1溶血-GPSer。越来越多的数据支持这样的假设，即溶血-PL发出钙通量的信号，因此，被假设为驱动PL触发器并抑制凋亡细胞中的APLT（通过流式细胞术研究的脂质运动来确定）。很少有人知道的身份或机制的阐述，介绍或释放这些PL信号的凋亡细胞识别。逐步地，假设：i）细胞凋亡期间氧化剂和/或PLA 2的活化导致信号转导GPCho和GPSer种类的加工，ii）APLT活性的丧失和活化的PL触发器使它们穿过血浆 在某些实施方案中，所述细胞以部分地由PL物质本身驱动的方式释放到细胞膜上，和iii）它们释放到培养基中，或保留在吞噬细胞信号的表面上，用于吞噬细胞募集和非炎性吞噬。