Ma Yuning, Chen Xia, Wang Mengyan, Meng Jianfen, Zhu Dehao, Chen Longfang, Xiao Yu, Yi Da, Shi Hui, Liu Honglei, Cheng Xiaobing, Su Yutong, Ye Junna, Chi Huihui, Zhou Zhuochao, Liu Tingting, Yang Chengde, Teng Jialin, Sun Yue, Jia Jinchao, Hu Qiongyi
Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Blood. 2025 Jul 31;146(5):612-627. doi: 10.1182/blood.2024024362.
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.
巨噬细胞活化综合征（MAS）被认为是由单核吞噬细胞系统的不适当增殖和活化引起的。成人斯蒂尔病（AOSD）的特征是中性粒细胞活化和细胞因子风暴，这可能导致严重的、潜在危及生命的MAS并发症。RNA测序显示，中性粒细胞可能发挥独特作用，并增强患有MAS的AOSD患者（AOSD-MAS）的固有免疫。在CpG诱导的继发性噬血细胞性淋巴组织细胞增生症（HLH）模型中，中性粒细胞的耗竭显著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，I/II型干扰素和JAK-STAT途径有显著富集。用鲁索替尼治疗10例难治性AOSD-MAS患者，炎症参数和临床症状得到缓解。RNA测序和体外试验证实，鲁索替尼抑制了异常的中性粒细胞胞外诱捕网形成（NETosis）和STAT3/STAT5信号传导。在体内，PAD4基因敲除进一步证实了NETosis在继发性HLH模型中的致病作用。此外，选择性抑制STAT3或STAT5可减轻全身炎症。在与JAK-STAT途径相关的基因中鉴定出10个功能变异体，然而，它们的临床相关性需要进一步验证。这些发现表明，鲁索替尼有可能通过广泛抑制JAK-STAT信号传导以及调节中性粒细胞活化和NETosis，促进难治性AOSD-MAS患者的疾病缓解。
