Zhao Hongshuai, Lan Mengfan, Huang Zikun, Fu Peng, Fu Biqi, Guo Yang, Li Junming, Luo Qing
Department of Clinical Laboratory, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.17, YongwaiZhengjie, Donghu District, Nanchang, 330006, Jiangxi, China.
Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China.
Clin Rheumatol. 2025 Jan;44(1):237-246. doi: 10.1007/s10067-024-07257-z. Epub 2024 Dec 13.
An increasing body of evidence suggests that N6-methyladenosine (m6A) plays a crucial role in the etiology of SLE. We focused on YTHDF2 expression in neutrophils and the relationship between YTHDF2 and the pathogenesis of SLE.
Sixty-one patients with SLE and 48 healthy controls (HC) were recruited, and their clinical characteristics were recorded. The mRNA levels of m6A "writers" (METTL3, METTL14, WTAP), "erasers" (FTO and ALKBH5), "readers" (YTHDF2), and inflammatory factors (interleukin-1β, interleukin-6, interleukin-8, and TNF-α) in neutrophils were determined by reverse transcription-quantitative PCR. The protein of YTHDF2 was determined by Western blotting. The correlations between the YTHDF2 in neutrophils of SLE patients and clinical features were examined by Spearman's method. YTHDF2 and TNF-α expression in neutrophils were examined after stimulation by SLE serums.
The mRNA expression of YTHDF2 in neutrophils was significantly decreased, and the protein level of YTHDF2 in neutrophils was decreased. The mRNA expression of YTHDF2 in neutrophils correlated with L% (r = 0.5796, P < 0.0001), LMR (r = 0.3524, P = 0.0062), WBC (r = - 0.3186, P = 0.0123), N (r = - 0.4141, P = 0.0010), N% (r = - 0.4813, P < 0.0001), NLR (r = - 0.5301, P < 0.0001), dNLR (r = - 0.4945, P < 0.0001), and SII (r = - 0.3930, P = 0.0019), which were suggested as the inflammatory conditions of SLE. In addition, the mRNA expression of TNF-α in neutrophils was significantly increased in SLE patients. Further analysis revealed that the mRNA expression of YTHDF2 in neutrophils was inversely correlated with TNF-α in SLE. Neutrophils from health control were significantly downregulated in their YTHDF2 expression and upregulated in their TNF-α expression following stimulation by serum from SLE patients.
This study indicates that the levels of YTHDF2 in peripheral blood neutrophils may be involved in the pathogenesis of SLE and could be a novel target for diagnosis and therapy. Key points • The mRNA expression of YTHDF2 in neutrophils of SLE and described that decreased mRNA of YTHDF2 in neutrophils correlated with L%, LMR, WBC, N, N%, NLR, dNLR, and SII. • The mRNA expression of TNF-α in neutrophils was significantly increased and correlated with YTHDF2 in SLE patients. • Neutrophils from health control were significantly downregulated in their YTHDF2 expression and upregulated in their TNF-α expression following stimulation by serum from SLE patients.
越来越多的证据表明，N6-甲基腺苷（m6A）在系统性红斑狼疮（SLE）的病因中起关键作用。我们重点研究了嗜中性粒细胞中YTHDF2的表达以及YTHDF2与SLE发病机制之间的关系。
招募了61例SLE患者和48名健康对照（HC），记录他们的临床特征。通过逆转录定量PCR测定嗜中性粒细胞中m6A“书写器”（METTL3、METTL14、WTAP）、“擦除器”（FTO和ALKBH5）、“读取器”（YTHDF2）和炎性因子（白细胞介素-1β、白细胞介素-6、白细胞介素-8和肿瘤坏死因子-α）的mRNA水平。通过蛋白质印迹法测定YTHDF2的蛋白质。采用Spearman法检测SLE患者嗜中性粒细胞中YTHDF2与临床特征之间的相关性。用SLE血清刺激后检测嗜中性粒细胞中YTHDF2和肿瘤坏死因子-α的表达。
嗜中性粒细胞中YTHDF2的mRNA表达显著降低，嗜中性粒细胞中YTHDF2的蛋白质水平降低。嗜中性粒细胞中YTHDF2的mRNA表达与L%（r = 0.5796，P < 0.0001）、LMR（r = 0.3524，P = 0.0062）、白细胞（WBC）（r = -0.3186，P = 0.0123）、中性粒细胞计数（N）（r = -0.4141，P = 0.0010）、中性粒细胞百分比（N%）（r = -0.4813，P < 0.0001）、中性粒细胞与淋巴细胞比值（NLR）（r = -0.5301，P < 0.0001）、动态NLR（dNLR）（r = -0.4945，P < 0.0001）和全身免疫炎症指数（SII）（r = -0.3930，P = 0.0019）相关，这些指标被认为是SLE的炎症状态指标。此外，SLE患者嗜中性粒细胞中肿瘤坏死因子-α的mRNA表达显著增加。进一步分析显示，SLE患者嗜中性粒细胞中YTHDF2的mRNA表达与肿瘤坏死因子-α呈负相关。用SLE患者血清刺激后，健康对照的嗜中性粒细胞YTHDF2表达显著下调，肿瘤坏死因子-α表达上调。
本研究表明，外周血嗜中性粒细胞中YTHDF2的水平可能参与SLE的发病机制，可能成为诊断和治疗的新靶点。要点：• 描述了SLE患者嗜中性粒细胞中YTHDF2的mRNA表达，且嗜中性粒细胞中YTHDF2的mRNA降低与L%、LMR、WBC、N、N%、NLR、dNLR和SII相关。• SLE患者嗜中性粒细胞中肿瘤坏死因子-α的mRNA表达显著增加，且与YTHDF2相关。• 用SLE患者血清刺激后，健康对照的嗜中性粒细胞YTHDF2表达显著下调，肿瘤坏死因子-α表达上调。
