Fan Xiubo, Ng Chin Teck, Guo Dianyang, Lim Frances, Tan Jia Chi, Law Annie, Goh Lim Hee, Poon Zhi Yong, Cheung Alice, Kong Say Li, Tan Michelle, Li Shang, Loh Alwin, James Anne, Lim Tony, Chen Jinmiao, Thumboo Julian, Hwang William, Low Andrea
Department of Clinical Translational Research, Singapore General Hospital, and SingHealth Duke-NUS Medicine Academic Clinical Programme, Duke-NUS Medical School, Singapore.
Department of Rheumatology and Immunology, Singapore General Hospital, and SingHealth Duke-NUS Medicine Academic Clinical Programme, Duke-NUS Medical School, Singapore.
Arthritis Rheumatol. 2023 Apr;75(4):553-566. doi: 10.1002/art.42383. Epub 2023 Feb 22.
To determine the efficacy of CXCL5 administration in lupus-prone MRL/lpr (Fas ) mice and elucidate its working mechanisms.
CXCL5 expression in blood (obtained from SLE patients and Fas mice) and major internal organs (obtained from Fas mice) was examined by Luminex, real-time polymerase chain reaction, and immunofluorescent staining analyses. Pharmacokinetic studies were performed in Fas mice and healthy Institute of Cancer Research mice. Efficacy of CXCL5 administration was demonstrated in Fas mice, and the working mechanism of CXCL5 treatment was elucidated by flow cytometry, Luminex, and RNA sequencing.
In SLE patients, serum CXCL5 levels were significantly lower than in healthy individuals (P < 0.0001) and negatively correlated with disease activity (P = 0.004). In Fas mice, disease severity progressed with age and was negatively associated with plasma CXCL5 levels. Intravenous administration of CXCL5 to Fas mice restored endogenous circulatory CXCL5, improved mice survival, and reduced anti-double-stranded DNA antibodies, proteinuria, lupus nephritis activity and chronicity indices, renal complements, and neutrophil extracellular traps over short-term (10 weeks) and long-term (2 years) time periods. In vitro and in vivo assays demonstrated that CXCL5 dictated neutrophil trafficking and suppressed neutrophil activation, degranulation, proliferation, and renal infiltration. Renal and splenic RNA sequencing further showed that CXCL5-mediated immunomodulation occurred by promoting energy production in renal-infiltrated immune cells, activating certain T cells, and reducing tissue fibrosis, granulocyte extravasation, complement components, and interferons. Further factorial design results indicated that CXCL5 appears to enhance host tolerability to cyclophosphamide in vulnerable individuals.
We found that serum CXCL5 levels were significantly lower in SLE patients than in healthy individuals and were negatively correlated with disease activity. By administering CXCL5 intravenously in a mouse model of lupus, mouse survival improved, and indices of disease activity reduced significantly. Taken together, these findings indicate CXCL5 administration may represent a novel myeloid/neutrophil-targeting therapy for SLE.
确定给予趋化因子配体5（CXCL5）对狼疮易感MRL/lpr（Fas）小鼠的疗效，并阐明其作用机制。
通过Luminex检测、实时聚合酶链反应及免疫荧光染色分析，检测血液（取自系统性红斑狼疮患者和Fas小鼠）及主要内脏器官（取自Fas小鼠）中CXCL5的表达。对Fas小鼠和健康的癌症研究所小鼠进行药代动力学研究。在Fas小鼠中证实给予CXCL5的疗效，并通过流式细胞术、Luminex检测及RNA测序阐明CXCL5治疗的作用机制。
在系统性红斑狼疮患者中，血清CXCL5水平显著低于健康个体（P＜0.0001），且与疾病活动度呈负相关（P = 0.004）。在Fas小鼠中，疾病严重程度随年龄进展，且与血浆CXCL5水平呈负相关。对Fas小鼠静脉注射CXCL5可恢复内源性循环CXCL5，提高小鼠存活率，并在短期（10周）和长期（2年）时间段内降低抗双链DNA抗体、蛋白尿、狼疮性肾炎活动度和慢性指数、肾脏补体及中性粒细胞胞外诱捕网。体外和体内试验表明，CXCL5决定中性粒细胞的迁移，并抑制中性粒细胞的激活、脱颗粒、增殖及肾脏浸润。肾脏和脾脏RNA测序进一步显示，CXCL5介导的免疫调节通过促进浸润肾脏的免疫细胞的能量产生、激活某些T细胞以及减少组织纤维化、粒细胞外渗、补体成分和干扰素来实现。进一步的析因设计结果表明，CXCL5似乎可增强易感个体对环磷酰胺的耐受性。
我们发现系统性红斑狼疮患者的血清CXCL5水平显著低于健康个体，且与疾病活动度呈负相关。通过在狼疮小鼠模型中静脉注射CXCL5，小鼠存活率提高，疾病活动指数显著降低。综上所述，这些发现表明给予CXCL5可能是一种针对系统性红斑狼疮的新型髓系/中性粒细胞靶向治疗方法。
