The Role of Efferocytosis in Inflammatory Arthritis

巨噬细胞增多在炎症性关节炎中的作用 摘要 风湿性关节炎（RA）是一种慢性炎症性疾病的滑膜关节，影响1在100人 全球范围内，仅在美国就有数百万人。我们注意到在炎症关节中有明显的凋亡细胞， 关节炎小鼠凋亡与凋亡细胞的吞噬作用（也称为“吞噬作用”）错综复杂地联系在一起。 目前的教条表明，增加凋亡细胞在组织中的持久性不可避免地导致病理。 然而，我们在本申请中提供的数据表明，这一教条值得进一步测试。首先，我们展示 全身注射凋亡细胞能有效地减轻关节炎小鼠的炎症。此外，无细胞 凋亡细胞上清液或甚至纯化的凋亡细胞释放的代谢物有效地抑制炎症反应。 关节炎最后，药理学或遗传性白细胞减少（不完全消融）也可减少 关节炎小鼠的炎症。在这里，我们将测试假设，减少红细胞增多症加重炎症 在关节炎中通过增加抗炎介质的释放（来自未清除的凋亡细胞）， 增强尸体处理/降解（由于吞噬细胞中尸体负载减少）。我们将继续 以下目标：1.使用具有药理学或遗传性红细胞减少的小鼠，我们将定量多个 关节炎中的疾病参数，确定发炎关节中凋亡细胞的数量， 吞噬细胞反应，并分析细胞清除率降低环境的代谢组学。2.生成并 验证了一种新的转基因小鼠模型，具有组织特异性，可诱导的红细胞减少。我们的研究结果 这将进一步加深我们对红细胞增多症在体内平衡和炎症中的理解，并可能开辟新的途径， 用于治疗类风湿性关节炎的治疗设计。

THE ROLE OF EFFEROCYTOSIS IN INFLAMMATORY ARTHRITIS Abstract Rheumatoid arthritis (RA) is a chronic inflammatory disease of the synovial joints which affects 1 in 100 people globally and millions in the US alone. We noted marked presence of apoptotic cells in the inflamed joints of arthritic mice. Apoptosis is intricately linked with phagocytosis of apoptotic cells, also known as ‘efferocytosis’. The current dogma suggests that increased apoptotic cell persistence in tissues inevitably leads to pathology. However, our data presented in this application suggest that this dogma warrants further testing. First, we show that systemic injection of apoptotic cells effectively alleviates inflammation in arthritic mice. Further, cell-free apoptotic cell supernatants or even purified apoptotic cell-released metabolites potently suppress inflammatory arthritis. Finally, pharmacologic or genetic efferocytosis reduction (not complete ablation) also reduce inflammation in arthritic mice. Here, we will test the hypothesis that reduced efferocytosis alleviates inflammation in arthritis through increased release of anti-inflammatory mediators (from uncleared apoptotic cells) and enhanced corpse processing/degradation (due to reduced corpse load in phagocytes). We will pursue the following aims: 1. Using mice with pharmacologic or genetic decrease in efferocytosis, we will quantify multiple disease parameters in arthritis, determine the numbers of apoptotic cells in the inflamed joints, analyze the phagocyte response, and analyze the metabolomics of reduced cell clearance environments. 2. Generate and validate a new transgenic mouse model with tissue-specific, inducible reduction of efferocytosis. Our findings will further our understanding of efferocytosis in homeostasis and inflammation and could open new avenues in therapeutic designs for the treatment of rheumatoid arthritis.