Cross A L, Hawkes J, Wright H L, Moots R J, Edwards S W
Institute of Ageing and Chronic Disease, Aintree University Hospital, Longmoor Lane, Liverpool, L9 7AL, UK.
Institute of Integrative Biology, University of Liverpool, Liverpool, L69 7ZB, UK.
Inflammopharmacology. 2020 Oct;28(5):1223-1235. doi: 10.1007/s10787-020-00715-5. Epub 2020 May 7.
Neutrophils are key players in the pathophysiological process underlying inflammatory conditions not only by release of tissue-damaging cytotoxic enzymes, reactive oxygen species (ROS) but also by secretion of important immunomodulatory chemokines and cytokines. Here, we report the effects of the novel agent APPA, undergoing formal clinical development for treatment of osteoarthritis, and its constituent components, apocynin (AP) and paeonol (PA) on a number of neutrophil functions, including effects on TNFα- expression and signalling. Neutrophils were treated with APPA (10-1000 µg/mL) prior to the measurement of cell functions, including ROS production, chemotaxis, apoptosis and surface receptor expression. Expression levels of several key genes and proteins were measured after incubation with APPA and the chromatin re-modelling agent, R848. APPA did not significantly affect phagocytosis, bacterial killing or expression of surface receptors, while chemotactic migration was affected only at the highest concentrations. However, APPA down-regulated neutrophil degranulation and ROS levels, and decreased the formation of neutrophil extracellular traps. APPA also decreased cytokine-stimulated gene expression, inhibiting both TNFα- and GM-CSF-induced cell signalling. APPA was as effective as infliximab in down-regulating chemokine and IL-6 expression following incubation with R848. Whilst APPA does not interfere with neutrophil host defence against infections, it does inhibit neutrophil degranulation, and cytokine-driven signalling pathways (e.g. autocrine signalling and NF-κB activation), processes that are associated with inflammation. These observations may explain the mechanisms by which APPA exerts anti-inflammatory effects and suggests a potential therapeutic role in inflammatory diseases in which neutrophils and TNFα signalling are important in pathology, such as rheumatoid arthritis.
中性粒细胞不仅通过释放具有组织损伤作用的细胞毒性酶、活性氧（ROS），还通过分泌重要的免疫调节趋化因子和细胞因子，在炎症性疾病的病理生理过程中发挥关键作用。在此，我们报告了正在进行骨关节炎治疗正式临床开发的新型药物APPA及其成分Apocynin（AP）和丹皮酚（PA）对多种中性粒细胞功能的影响，包括对TNFα表达和信号传导的影响。在测量细胞功能（包括ROS产生、趋化性、凋亡和表面受体表达）之前，用APPA（10 - 1000μg/mL）处理中性粒细胞。在用APPA和染色质重塑剂R848孵育后，测量几个关键基因和蛋白质的表达水平。APPA对吞噬作用、细菌杀伤或表面受体表达没有显著影响，而趋化迁移仅在最高浓度时受到影响。然而，APPA下调了中性粒细胞脱颗粒和ROS水平，并减少了中性粒细胞胞外陷阱的形成。APPA还降低了细胞因子刺激的基因表达，抑制了TNFα和GM - CSF诱导的细胞信号传导。在与R848孵育后，APPA在下调趋化因子和IL - 6表达方面与英夫利昔单抗一样有效。虽然APPA不干扰中性粒细胞对感染的宿主防御，但它确实抑制中性粒细胞脱颗粒以及细胞因子驱动的信号通路（如自分泌信号传导和NF - κB激活），这些过程与炎症相关。这些观察结果可能解释了APPA发挥抗炎作用的机制，并提示其在类风湿关节炎等中性粒细胞和TNFα信号传导在病理过程中起重要作用的炎症性疾病中具有潜在的治疗作用。
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