A pathway regulating neutrophil integrin inactivation and its contribution to inflammation

人体的免疫细胞会产生炎症，作为防御感染的一部分。但有时，即使在没有感染的情况下，免疫细胞也会产生炎症。慢性炎症性疾病，如类风湿性关节炎或多发性硬化症，造成许多痛苦，并对世界各地的卫生服务造成巨大的消耗。要产生炎症，一种名为中性粒细胞的白细胞是必不可少的。中性粒细胞是最常见的白细胞类型。中性粒细胞从血流中被招募到感染或受伤的地方。为了离开血流，中性粒细胞变得粘性：它们在转运之前附着在血管壁的内侧。这个过程依赖于特定的细胞表面分子，整合素。整合素以“粘性”(活性)和“非粘性”(非活性)构象存在。已经知道，整合素的缺乏，或者它们无法激活，会干扰中性粒细胞在感染部位的招募。少数研究分析了在实验中被永久激活的整合素。这些激活的整合素也不支持中性粒细胞的招募。我们最近发现，一种名为ARAP3的细胞调节因子对于调节中性粒细胞整合素很重要，使激活的整合素变得不活跃。ARAP3的缺失改变了中性粒细胞的活性。例如，它干扰了中性粒细胞在试管中的迁移，因为中性粒细胞过于牢固地附着在底层支撑物上。我们认为，中性粒细胞需要能够激活和灭活其整合素，“微调”整合素活性，以便在体内组织中最佳迁移。因此，ARAP3的缺失也可能干扰中性粒细胞的募集，最终导致炎症。我们将在试管、中性粒细胞募集和炎症模型中研究这一点。我们认为ARAP3是一个很好的抗炎靶点。这项工作将为针对慢性炎症的新治疗方法奠定基础。

The body's immune cells generate inflammation as part of their defence against infections. But sometimes, immune cells generate inflammation even in the absence of infection. Chronic inflammatory conditions, such as rheumatoid arthritis or multiple sclerosis cause much suffering and pose a massive drain on health services world-wide. To generate inflammation, a type of white blood cell called the neutrophil is essential. Neutrophils are the most common type of white blood cell. Neutrophils are recruited from the blood stream to sites of infection or injury. In order to leave the bloodstream, neutrophils become sticky: they adhere to the inside of the wall of the blood vessel before they transmigrate. This process relies on particular cell surface molecules, the integrins. Integrins exist in a "sticky" (active) and a "non-sticky" (inactive) conformation. It's already known that absence of integrins, or their inability to become activated interferes with the recruitment of neutrophils to sites of infection. A small number of studies analysed integrins that were experimentally rendered permanently active. These activated integrins, too, did not support neutrophil recruitment. We recently showed that a cellular regulator called ARAP3 is important for the regulation of neutrophil integrins, allowing activated integrins to become inactive. Loss of ARAP3 changes the activity profile of the neutrophil. For example, it interferes with migration in the test tube, as neutrophils adhere too firmly to the underlying support. We think that neutrophils need to be able to activate, and inactivate their integrins, "fine-tuning" integrin activity for optimal migration through the body's tissues. Therefore, loss of ARAP3 may also interfere with neutrophil recruitment, and ultimately inflammation. We will study this in the test tube and in models for neutrophil recruitment and for inflammation. We think that ARAP3 is a good target for combating inflammation. This work will build the foundations for new therapeutic approaches targeting chronic inflammation.