Regulation of type I interferon signature by VGLL3 in the fibroblast-like synoviocytes of rheumatoid arthritis patients via targeting the Hippo pathway
Abstract Background The upregulation of interferon (IFN)-stimulated genes induced by type I IFNs (namely type I IFN signature) in rheumatoid arthritis (RA) patients had implications in early diagnosis and prediction of therapy responses. However, factors that modulate the type I IFN signature in RA...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-08-01
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| Series: | Arthritis Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13075-022-02880-0 |
| _version_ | 1811215714496806912 |
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| author | Yu Du Ran Cui Na Tian Miao Chen Xian-Long Zhang Sheng-Ming Dai |
| author_facet | Yu Du Ran Cui Na Tian Miao Chen Xian-Long Zhang Sheng-Ming Dai |
| author_sort | Yu Du |
| collection | DOAJ |
| description | Abstract Background The upregulation of interferon (IFN)-stimulated genes induced by type I IFNs (namely type I IFN signature) in rheumatoid arthritis (RA) patients had implications in early diagnosis and prediction of therapy responses. However, factors that modulate the type I IFN signature in RA are largely unknown. In this study, we aim to explore the involvement of VGLL3, a homologue of the vestigial-like gene in Drosophila and a putative regulator of the Hippo pathway, in the modulation of type I IFN signature in the fibroblast-like synoviocytes (FLS) of RA patients. Methods FLS were isolated from RA and osteoarthritis (OA) patients. Expression of VGLL3 in the synovial tissues and FLS was analyzed by immunohistochemistry and PCR. RNA sequencing was performed in RA-FLS upon VGLL3 overexpression. The expression of IFN-stimulated genes was examined by PCR and Western blotting. Results VGLL3 was upregulated in the RA synovium and RA-FLS compared to OA. Overexpression of VGLL3 promoted the expression of IFN-stimulated genes in RA-FLS. The expression of STAT1 and MX1 was also upregulated in RA synovium compared to OA and was associated with the expression of VGLL3 in RA and OA patients. VGLL3 promoted the IRF3 activation and IFN-β1 expression in RA-FLS. Increased IFN-β1 induced the expression of IFN-stimulated genes in RA-FLS in an autocrine manner. VGLL3 also modulated the expression of the Hippo pathway molecules WWTR1 and AMOTL2, which mediated the regulation of IRF3 activation and IFN-β1 production by VGLL3 in RA-FLS. Conclusions VGLL3 drives the IRF3-induced IFN-β1 expression in RA-FLS by inhibiting WWTR1 expression and subsequently promotes the type I IFN signature expression in RA-FLS through autocrine IFN-β1 signaling. |
| first_indexed | 2024-04-12T06:28:12Z |
| format | Article |
| id | doaj.art-734a0ec6fe9c4ce3a8e3e193d3ab8e06 |
| institution | Directory Open Access Journal |
| issn | 1478-6362 |
| language | English |
| last_indexed | 2024-04-12T06:28:12Z |
| publishDate | 2022-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Arthritis Research & Therapy |
| spelling | doaj.art-734a0ec6fe9c4ce3a8e3e193d3ab8e062022-12-22T03:44:06ZengBMCArthritis Research & Therapy1478-63622022-08-0124111210.1186/s13075-022-02880-0Regulation of type I interferon signature by VGLL3 in the fibroblast-like synoviocytes of rheumatoid arthritis patients via targeting the Hippo pathwayYu Du0Ran Cui1Na Tian2Miao Chen3Xian-Long Zhang4Sheng-Ming Dai5Department of Rheumatology and Immunology, Shanghai Jiao Tong University Affiliated Sixth People’s HospitalDepartment of Rheumatology and Immunology, Shanghai Jiao Tong University Affiliated Sixth People’s HospitalDepartment of Rheumatology and Immunology, Shanghai Jiao Tong University Affiliated Sixth People’s HospitalDepartment of Rheumatology and Immunology, Shanghai Jiao Tong University Affiliated Sixth People’s HospitalDepartment of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s HospitalDepartment of Rheumatology and Immunology, Shanghai Jiao Tong University Affiliated Sixth People’s HospitalAbstract Background The upregulation of interferon (IFN)-stimulated genes induced by type I IFNs (namely type I IFN signature) in rheumatoid arthritis (RA) patients had implications in early diagnosis and prediction of therapy responses. However, factors that modulate the type I IFN signature in RA are largely unknown. In this study, we aim to explore the involvement of VGLL3, a homologue of the vestigial-like gene in Drosophila and a putative regulator of the Hippo pathway, in the modulation of type I IFN signature in the fibroblast-like synoviocytes (FLS) of RA patients. Methods FLS were isolated from RA and osteoarthritis (OA) patients. Expression of VGLL3 in the synovial tissues and FLS was analyzed by immunohistochemistry and PCR. RNA sequencing was performed in RA-FLS upon VGLL3 overexpression. The expression of IFN-stimulated genes was examined by PCR and Western blotting. Results VGLL3 was upregulated in the RA synovium and RA-FLS compared to OA. Overexpression of VGLL3 promoted the expression of IFN-stimulated genes in RA-FLS. The expression of STAT1 and MX1 was also upregulated in RA synovium compared to OA and was associated with the expression of VGLL3 in RA and OA patients. VGLL3 promoted the IRF3 activation and IFN-β1 expression in RA-FLS. Increased IFN-β1 induced the expression of IFN-stimulated genes in RA-FLS in an autocrine manner. VGLL3 also modulated the expression of the Hippo pathway molecules WWTR1 and AMOTL2, which mediated the regulation of IRF3 activation and IFN-β1 production by VGLL3 in RA-FLS. Conclusions VGLL3 drives the IRF3-induced IFN-β1 expression in RA-FLS by inhibiting WWTR1 expression and subsequently promotes the type I IFN signature expression in RA-FLS through autocrine IFN-β1 signaling.https://doi.org/10.1186/s13075-022-02880-0Rheumatoid arthritisInterferon betaType I interferon signatureHippo pathway |
| spellingShingle | Yu Du Ran Cui Na Tian Miao Chen Xian-Long Zhang Sheng-Ming Dai Regulation of type I interferon signature by VGLL3 in the fibroblast-like synoviocytes of rheumatoid arthritis patients via targeting the Hippo pathway Arthritis Research & Therapy Rheumatoid arthritis Interferon beta Type I interferon signature Hippo pathway |
| title | Regulation of type I interferon signature by VGLL3 in the fibroblast-like synoviocytes of rheumatoid arthritis patients via targeting the Hippo pathway |
| title_full | Regulation of type I interferon signature by VGLL3 in the fibroblast-like synoviocytes of rheumatoid arthritis patients via targeting the Hippo pathway |
| title_fullStr | Regulation of type I interferon signature by VGLL3 in the fibroblast-like synoviocytes of rheumatoid arthritis patients via targeting the Hippo pathway |
| title_full_unstemmed | Regulation of type I interferon signature by VGLL3 in the fibroblast-like synoviocytes of rheumatoid arthritis patients via targeting the Hippo pathway |
| title_short | Regulation of type I interferon signature by VGLL3 in the fibroblast-like synoviocytes of rheumatoid arthritis patients via targeting the Hippo pathway |
| title_sort | regulation of type i interferon signature by vgll3 in the fibroblast like synoviocytes of rheumatoid arthritis patients via targeting the hippo pathway |
| topic | Rheumatoid arthritis Interferon beta Type I interferon signature Hippo pathway |
| url | https://doi.org/10.1186/s13075-022-02880-0 |
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