Macrophage activation syndrome (MAS) is believed to be caused by inappropriate proliferation and activation of the mononuclear phagocytic system. Adult-onset Still disease (AOSD) is characterized by neutrophil activation and a cytokine storm, which can lead to the severe and potentially life-threatening complication of MAS. RNA sequencing revealed that neutrophils may play a distinct role and enhance the innate immunity of patients with AOSD with MAS (AOSD-MAS). In the CpG-induced secondary hemophagocytic lymphohistiocytosis (HLH) model, the depletion of neutrophils significantly reduced cytokine levels with effects comparable with monocyte depletion. Significant enrichment was observed in the type I/II interferon and JAK-STAT pathways in neutrophils from patients with AOSD-MAS. Treatment of 10 patients with refractory AOSD-MAS with ruxolitinib led to the resolution of inflammatory parameters and clinical symptoms. RNA sequencing and ex vivo assays confirmed that ruxolitinib suppressed aberrant NETosis and STAT3/STAT5 signaling. In vivo, PAD4 knockout further confirmed the pathogenic role of NETosis in a secondary HLH model. Moreover, the selective inhibition of STAT3 or STAT5 alleviated systemic inflammation. Ten functional variants were identified in genes related to the JAK-STAT pathway, however, their clinical relevance requires further validation. These findings suggest that ruxolitinib has the potential to facilitate disease remission in patients with refractory AOSD-MAS by broadly inhibiting JAK-STAT signaling and modulating neutrophil activation and NETosis.

中文翻译：

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Ruxolitinib 靶向 JAK-STAT 信号转导调节难治性巨噬细胞激活综合征中的中性粒细胞激活

巨噬细胞激活综合征 （MAS） 被认为是由单核吞噬系统的不适当增殖和激活引起的。成人发病静止病 （AOSD） 的特征是中性粒细胞激活和细胞因子风暴，这可能导致 MAS 的严重且可能危及生命的并发症。RNA 测序显示，中性粒细胞可能发挥独特的作用，增强 AOSD 伴 MAS（AOSD-MAS）患者的先天免疫力。在 CpG 诱导的继发性噬血细胞淋巴组织细胞增多症 （HLH） 模型中，中性粒细胞的耗竭显着降低了细胞因子水平，其效果与单核细胞耗竭相当。在 AOSD-MAS 患者的中性粒细胞中观察到 I/II 型干扰素和 JAK-STAT 通路显着富集。用鲁索替尼治疗 10 名难治性 AOSD-MAS 患者，导致炎症参数和临床症状的消退。RNA 测序和离体检测证实，鲁索替尼抑制异常的 NETosis 和 STAT3/STAT5 信号传导。在体内，PAD4 敲除进一步证实了 NETosis 在继发 HLH 模型中的致病作用。此外，选择性抑制 STAT3 或 STAT5 减轻了全身炎症。在与 JAK-STAT 通路相关的基因中鉴定出 10 个功能变异，但它们的临床相关性需要进一步验证。这些发现表明，ruxolitinib 有可能通过广泛抑制 JAK-STAT 信号传导和调节中性粒细胞激活和 NETosis 来促进难治性 AOSD-MAS 患者的疾病缓解。