Potential role of RhoA GTPase regulation in type interferon signaling in systemic lupus erythematosus.
Potential role of RhoA GTPase regulation in type interferon signaling in systemic lupus erythematosus.
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DOI：
10.1186/s13075-024-03263-3
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发表时间：
2024-01-20
影响因子：
4.9
通讯作者：
Bucala, Richard
中科院分区：
文献类型：
--
作者：
Fan, Wei;Wei, Bo;Chen, Xuyan;Zhang, Yi;Xiao, Pingping;Li, Kaiyan;Zhang, Yi qin;Huang, Jinmei;Leng, Lin;Bucala, Richard
系统性红斑狼疮(SLE)是一种自身免疫性疾病，其特征是I型干扰素途径异常激活，导致组织炎症和器官损伤。我们探讨了RhoA GTP酶在I型干扰素激活途径中的作用，为靶向GTP酶信号转导治疗SLE提供了潜在的依据。提取SLE患者和健康对照组外周血单个核细胞(PBMC)总RNA，用SYBR Green定量逆转录聚合酶链式反应检测RhoA和干扰素刺激基因的mRNA表达水平。采用干扰素-α刺激反应元件(ISRE)-荧光素酶报告基因分析和Western blotting检测RhoA的生物学功能。酶联免疫分析法检测C-X-C基序趋化因子配体10(CXCL10)蛋白表达。我们的研究表明，SLE患者PBMC中RhoA的表达明显高于健康对照组，并与I型干扰素评分和I型干扰素刺激基因(ISGs)的表达水平呈正相关。SiRNA介导的RhoA和RhoA/ROCK抑制剂Y27632抑制I型干扰素诱导的ISRE活性、信号转导和转录激活因子1(STAT-1)的磷酸化以及CXCL10和2‘-5’-寡腺苷合成酶1(OAS1)的表达。最后，我们验证了Y27632可以显著下调SLE患者PBMC中OAS1和CXCL10的表达水平。我们的研究表明，RhoA正向调节I型干扰素反应通路的激活。降低RhoA的表达水平可抑制I型干扰素系统的异常激活，RhoA/ROCK抑制剂Y27632可减少SLE PBMC中异常的I型干扰素信号，提示靶向RhoA GTPase治疗SLE的可能性。网上版载有补充材料，可在10.1186/s13075-024-03263-3查阅。
Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by abnormal activation of the type I interferon (IFN) pathway, which results in tissue inflammation and organ damage. We explored the role of the RhoA GTPase in the type I IFN activation pathway to provide a potential basis for targeting GTPase signaling for the treatment of SLE. Total RNA was extracted from peripheral blood mononuclear cells (PBMCs) of SLE patients and healthy controls, and the mRNA expression levels of RhoA and IFN-stimulated genes were measured by SYBR Green quantitative reverse transcriptase-polymerase chain reaction. IFN-a-stimulated response element (ISRE)-luciferase reporter gene assays and Western blotting were conducted to assess the biologic function of RhoA. An enzyme-linked immunoassay (ELISA) measured C-X-C motif chemokine ligand 10 (CXCL10) protein expression. Our studies demonstrate that the expression of RhoA in the PBMCs of SLE subjects was significantly higher than in healthy controls and positively correlated with type I IFN scores and type I IFN-stimulated gene (ISGs) expression levels. SiRNA-mediated knockdown of RhoA and the RhoA/ROCK inhibitor Y27632 reduced the activity of the type I IFN-induced ISRE, the signal transducer and activator of transcription 1 (STAT-1) phosphorylation, and the expression of CXCL10 and 2′-5′-oligoadenylate synthetase 1 (OAS1). Finally, we verified that Y27632 could significantly down-regulate the OAS1 and CXCL10 expression levels in the PBMCs of SLE patients. Our study shows that RhoA positively regulates the activation of the type I IFN response pathway. Reducing the expression level of RhoA inhibits the abnormal activation of the type I IFN system, and the RhoA/ROCK inhibitor Y27632 decreases aberrant type I IFN signaling in SLE PBMCs, suggesting the possibility of targeting the RhoA GTPase for the treatment of SLE. The online version contains supplementary material available at 10.1186/s13075-024-03263-3.
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影响因子：
13.3
作者：
Chiche, Laurent;Jourde-Chiche, Noemie;Whalen, Elizabeth;Presnell, Scott;Gersuk, Vivian;Dang, Kristen;Anguiano, Esperanza;Quinn, Charlie;Burtey, Stephane;Berland, Yvon;Kaplanski, Gilles;Harle, Jean-Robert;Pascual, Virginia;Chaussabel, Damien
通讯作者：
Chaussabel, Damien
影响因子：
27.4
作者：
Houssiau, Frederic A.;Thanou, Aikaterini;Lucas Tee, Michael
通讯作者：
Lucas Tee, Michael
影响因子：
27.4
作者：
Landolt-Marticorena, C.;Bonventi, G.;Wither, J.
通讯作者：
Wither, J.
影响因子：
4.4
作者：
Li, Yansong;Harada, Tatsuhiro;Tsokos, George C.
通讯作者：
Tsokos, George C.
系统性红斑狼疮
影响因子：
81.5
作者：
Kaul, Arvind;Gordon, Caroline;Hughes, Graham
通讯作者：
Hughes, Graham