Potential role of RhoA GTPase regulation in type interferon signaling in systemic lupus erythematosus
Abstract Objective 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...
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| Language: | English |
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BMC
2024-01-01
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| Series: | Arthritis Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13075-024-03263-3 |
| _version_ | 1827377201477058560 |
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| author | Wei Fan Bo Wei Xuyan Chen Yi Zhang Pingping Xiao Kaiyan Li Yi qin Zhang Jinmei Huang Lin Leng Richard Bucala |
| author_facet | Wei Fan Bo Wei Xuyan Chen Yi Zhang Pingping Xiao Kaiyan Li Yi qin Zhang Jinmei Huang Lin Leng Richard Bucala |
| author_sort | Wei Fan |
| collection | DOAJ |
| description | Abstract Objective 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. Methods 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. Results 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. Conclusion 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. |
| first_indexed | 2024-03-08T12:35:34Z |
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| id | doaj.art-99f0d7bfdab2483e9b9996dfe8d98fee |
| institution | Directory Open Access Journal |
| issn | 1478-6362 |
| language | English |
| last_indexed | 2024-03-08T12:35:34Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Arthritis Research & Therapy |
| spelling | doaj.art-99f0d7bfdab2483e9b9996dfe8d98fee2024-01-21T12:29:19ZengBMCArthritis Research & Therapy1478-63622024-01-0126111110.1186/s13075-024-03263-3Potential role of RhoA GTPase regulation in type interferon signaling in systemic lupus erythematosusWei Fan0Bo Wei1Xuyan Chen2Yi Zhang3Pingping Xiao4Kaiyan Li5Yi qin Zhang6Jinmei Huang7Lin Leng8Richard Bucala9Department of Rheumatology and Immunology, the Second Affiliated Hospital of Xiamen Medical College, Xiamen Medical CollegeDepartment of Rheumatology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen UniversityDepartment of Rheumatology and Immunology, the Second Affiliated Hospital of Xiamen Medical College, Xiamen Medical CollegeDepartment of Rheumatology and Immunology, the Second Affiliated Hospital of Xiamen Medical College, Xiamen Medical CollegeDepartment of Rheumatology and Immunology, the Second Affiliated Hospital of Xiamen Medical College, Xiamen Medical CollegeDepartment of Rheumatology and Immunology, the Second Affiliated Hospital of Xiamen Medical College, Xiamen Medical CollegeDepartment of Nephrology, the Second Affiliated Hospital of Xiamen Medical College, Xiamen Medical CollegeDepartment of Rheumatology and Immunology, the Second Affiliated Hospital of Xiamen Medical College, Xiamen Medical CollegeDepartment of Internal Medicine, Yale University School of MedicineDepartment of Internal Medicine, Yale University School of MedicineAbstract Objective 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. Methods 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. Results 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. Conclusion 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.https://doi.org/10.1186/s13075-024-03263-3AutoimmunitySystemic lupus erythematosusRhoAType I IFNRhoA/ROCK inhibitor |
| spellingShingle | Wei Fan Bo Wei Xuyan Chen Yi Zhang Pingping Xiao Kaiyan Li Yi qin Zhang Jinmei Huang Lin Leng Richard Bucala Potential role of RhoA GTPase regulation in type interferon signaling in systemic lupus erythematosus Arthritis Research & Therapy Autoimmunity Systemic lupus erythematosus RhoA Type I IFN RhoA/ROCK inhibitor |
| title | Potential role of RhoA GTPase regulation in type interferon signaling in systemic lupus erythematosus |
| title_full | Potential role of RhoA GTPase regulation in type interferon signaling in systemic lupus erythematosus |
| title_fullStr | Potential role of RhoA GTPase regulation in type interferon signaling in systemic lupus erythematosus |
| title_full_unstemmed | Potential role of RhoA GTPase regulation in type interferon signaling in systemic lupus erythematosus |
| title_short | Potential role of RhoA GTPase regulation in type interferon signaling in systemic lupus erythematosus |
| title_sort | potential role of rhoa gtpase regulation in type interferon signaling in systemic lupus erythematosus |
| topic | Autoimmunity Systemic lupus erythematosus RhoA Type I IFN RhoA/ROCK inhibitor |
| url | https://doi.org/10.1186/s13075-024-03263-3 |
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