Key Points NADPH oxidase hyperactivity accompanies autoinflammation in Pstpip2cmo mice. This hyperactivity is cell intrinsic and not caused by an inflamed environment. NADPH oxidase deletion prevents autoinflammatory bone damage in Pstpip2cmo mice. Autoinflammatory diseases are characterized by dysregulation of the innate immune system, leading to spontaneous inflammation. Pstpip2cmo mouse strain is a well-characterized model of this class of disorders. Because of the mutation leading to the lack of adaptor protein PSTPIP2, these animals suffer from autoinflammatory chronic multifocal osteomyelitis similar to several human syndromes. Current evidence suggests that it is driven by hyperproduction of IL-1β by neutrophil granulocytes. In this study, we show that in addition to IL-1β, PSTPIP2 also negatively regulates pathways governing reactive oxygen species generation by neutrophil NOX2 NADPH oxidase. Pstpip2cmo neutrophils display highly elevated superoxide production in response to a range of stimuli. Inactivation of NOX2 NADPH oxidase in Pstpip2cmo mice did not affect IL-1β levels, and the autoinflammatory process was initiated with similar kinetics. However, the bone destruction was almost completely alleviated, suggesting that dysregulated NADPH oxidase activity is a key factor promoting autoinflammatory bone damage in Pstpip2cmo mice.

中文翻译：

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失调的 NADPH 氧化酶促进自身炎症性骨髓炎小鼠模型的骨损伤

关键点 NADPH 氧化酶过度活跃伴随着 Pstpip2cmo 小鼠的自身炎症。这种过度活跃是细胞内在的，而不是由发炎的环境引起的。NADPH 氧化酶缺失可防止 Pstpip2cmo 小鼠的自身炎症性骨损伤。自身炎症性疾病的特征是先天免疫系统失调，导致自发性炎症。Pstpip2cmo 小鼠品系是此类疾病的典型模型。由于突变导致缺乏接头蛋白 PSTPIP2，这些动物患有类似于几种人类综合征的自身炎症性慢性多灶性骨髓炎。目前的证据表明，它是由中性粒细胞过度产生 IL-1β 驱动的。在这项研究中，我们表明除了 IL-1β，PSTPIP2 还负向调节控制中性粒细胞 NOX2 NADPH 氧化酶产生活性氧的途径。Pstpip2cmo 中性粒细胞在响应一系列刺激时显示出高度升高的超氧化物产量。Pstpip2cmo 小鼠中 NOX2 NADPH 氧化酶的失活不影响 IL-1β 水平，并且自身炎症过程以类似的动力学开始。然而，骨破坏几乎完全缓解，表明失调的 NADPH 氧化酶活性是促进 Pstpip2cmo 小鼠自身炎症性骨损伤的关键因素。并且自身炎症过程以类似的动力学开始。然而，骨破坏几乎完全缓解，表明失调的 NADPH 氧化酶活性是促进 Pstpip2cmo 小鼠自身炎症性骨损伤的关键因素。并且自身炎症过程以类似的动力学开始。然而，骨破坏几乎完全缓解，表明失调的 NADPH 氧化酶活性是促进 Pstpip2cmo 小鼠自身炎症性骨损伤的关键因素。