Role of high-temperature requirement serine protease A 2 in rheumatoid inflammation
Abstract Background High-temperature requirement serine protease A 2 (HtrA2) is known to be involved in growth, unfolded protein response to stress, apoptosis, and autophagy. However, whether HtrA2 controls inflammation and immune response remains elusive. Methods Expression of HtrA2 in the synovial...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-06-01
|
| Series: | Arthritis Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13075-023-03081-z |
| _version_ | 1797806571851350016 |
|---|---|
| author | Gi Heon Jeong Min-Kyung Nam Wonhee Hur Seolhee Heo Saseong Lee Eunbyeol Choi Jae Hyung Park Youngjae Park Wan-Uk Kim Hyangshuk Rhim Seung-Ah Yoo |
| author_facet | Gi Heon Jeong Min-Kyung Nam Wonhee Hur Seolhee Heo Saseong Lee Eunbyeol Choi Jae Hyung Park Youngjae Park Wan-Uk Kim Hyangshuk Rhim Seung-Ah Yoo |
| author_sort | Gi Heon Jeong |
| collection | DOAJ |
| description | Abstract Background High-temperature requirement serine protease A 2 (HtrA2) is known to be involved in growth, unfolded protein response to stress, apoptosis, and autophagy. However, whether HtrA2 controls inflammation and immune response remains elusive. Methods Expression of HtrA2 in the synovial tissue of patients was examined using immunohistochemistry and immunofluorescence staining. Enzyme-linked immunosorbent assay was used to determine the concentrations of HtrA2, interleukin-6 (IL-6), interleukin-8 (IL-8), chemokine (C-C motif) ligand 2 (CCL2), and tumor necrosis factor α (TNFα). Synoviocyte survival was assessed by MTT assay. For the downregulation of HtrA2 transcripts, cells were transfected with HtrA2 siRNA. Results We found that the concentration of HtrA2 was elevated in rheumatoid arthritis (RA) synovial fluid (SF) than in osteoarthritis (OA) SF, and its concentrations were correlated with the number of immune cells in the RA SF. Interestingly, HtrA2 levels in the SF of RA patients were elevated in proportion to synovitis severity and correlated with the expression of proinflammation cytokines and chemokines, such as IL-6, IL-8, and CCL2. In addition, HtrA2 was highly expressed in RA synovium and primary synoviocytes. RA synoviocytes released HtrA2 when stimulated with ER stress inducers. Knockdown of HtrA2 inhibited the IL1β-, TNFα-, and LPS-induced release of proinflammatory cytokines and chemokines by RA synoviocytes. Conclusion HtrA2 is a novel inflammatory mediator and a potential target for the development of an anti-inflammation therapy for RA. |
| first_indexed | 2024-03-13T06:09:17Z |
| format | Article |
| id | doaj.art-590509797c3842388121f55d887021bf |
| institution | Directory Open Access Journal |
| issn | 1478-6362 |
| language | English |
| last_indexed | 2024-03-13T06:09:17Z |
| publishDate | 2023-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Arthritis Research & Therapy |
| spelling | doaj.art-590509797c3842388121f55d887021bf2023-06-11T11:21:23ZengBMCArthritis Research & Therapy1478-63622023-06-0125111210.1186/s13075-023-03081-zRole of high-temperature requirement serine protease A 2 in rheumatoid inflammationGi Heon Jeong0Min-Kyung Nam1Wonhee Hur2Seolhee Heo3Saseong Lee4Eunbyeol Choi5Jae Hyung Park6Youngjae Park7Wan-Uk Kim8Hyangshuk Rhim9Seung-Ah Yoo10Department of Biomedicine & Health Sciences, Department of Medical Life Sciences, College of Medicine, The Catholic University of KoreaDepartment of Biomedicine & Health Sciences, Department of Medical Life Sciences, College of Medicine, The Catholic University of KoreaDivision of Chronic Viral Diseases, Center for Emerging Virus Research, Korea National Institute of HealthDepartment of Biomedicine & Health Sciences, Department of Medical Life Sciences, College of Medicine, The Catholic University of KoreaCenter for Integrative Rheumatoid Transcriptomics and Dynamics, The Catholic University of KoreaDepartment of Biomedicine & Health Sciences, Department of Medical Life Sciences, College of Medicine, The Catholic University of KoreaSchool of Chemical Engineering, College of Engineering, Sungkyunkwan UniversityDepartment of Internal Medicine, The Catholic University of KoreaDepartment of Biomedicine & Health Sciences, Department of Medical Life Sciences, College of Medicine, The Catholic University of KoreaDepartment of Biomedicine & Health Sciences, Department of Medical Life Sciences, College of Medicine, The Catholic University of KoreaDepartment of Biomedicine & Health Sciences, Department of Medical Life Sciences, College of Medicine, The Catholic University of KoreaAbstract Background High-temperature requirement serine protease A 2 (HtrA2) is known to be involved in growth, unfolded protein response to stress, apoptosis, and autophagy. However, whether HtrA2 controls inflammation and immune response remains elusive. Methods Expression of HtrA2 in the synovial tissue of patients was examined using immunohistochemistry and immunofluorescence staining. Enzyme-linked immunosorbent assay was used to determine the concentrations of HtrA2, interleukin-6 (IL-6), interleukin-8 (IL-8), chemokine (C-C motif) ligand 2 (CCL2), and tumor necrosis factor α (TNFα). Synoviocyte survival was assessed by MTT assay. For the downregulation of HtrA2 transcripts, cells were transfected with HtrA2 siRNA. Results We found that the concentration of HtrA2 was elevated in rheumatoid arthritis (RA) synovial fluid (SF) than in osteoarthritis (OA) SF, and its concentrations were correlated with the number of immune cells in the RA SF. Interestingly, HtrA2 levels in the SF of RA patients were elevated in proportion to synovitis severity and correlated with the expression of proinflammation cytokines and chemokines, such as IL-6, IL-8, and CCL2. In addition, HtrA2 was highly expressed in RA synovium and primary synoviocytes. RA synoviocytes released HtrA2 when stimulated with ER stress inducers. Knockdown of HtrA2 inhibited the IL1β-, TNFα-, and LPS-induced release of proinflammatory cytokines and chemokines by RA synoviocytes. Conclusion HtrA2 is a novel inflammatory mediator and a potential target for the development of an anti-inflammation therapy for RA.https://doi.org/10.1186/s13075-023-03081-zRheumatoid arthritisFibroblast-like synoviocytesHigh-temperature requirement serine protease AInflammation |
| spellingShingle | Gi Heon Jeong Min-Kyung Nam Wonhee Hur Seolhee Heo Saseong Lee Eunbyeol Choi Jae Hyung Park Youngjae Park Wan-Uk Kim Hyangshuk Rhim Seung-Ah Yoo Role of high-temperature requirement serine protease A 2 in rheumatoid inflammation Arthritis Research & Therapy Rheumatoid arthritis Fibroblast-like synoviocytes High-temperature requirement serine protease A Inflammation |
| title | Role of high-temperature requirement serine protease A 2 in rheumatoid inflammation |
| title_full | Role of high-temperature requirement serine protease A 2 in rheumatoid inflammation |
| title_fullStr | Role of high-temperature requirement serine protease A 2 in rheumatoid inflammation |
| title_full_unstemmed | Role of high-temperature requirement serine protease A 2 in rheumatoid inflammation |
| title_short | Role of high-temperature requirement serine protease A 2 in rheumatoid inflammation |
| title_sort | role of high temperature requirement serine protease a 2 in rheumatoid inflammation |
| topic | Rheumatoid arthritis Fibroblast-like synoviocytes High-temperature requirement serine protease A Inflammation |
| url | https://doi.org/10.1186/s13075-023-03081-z |
| work_keys_str_mv | AT giheonjeong roleofhightemperaturerequirementserineproteasea2inrheumatoidinflammation AT minkyungnam roleofhightemperaturerequirementserineproteasea2inrheumatoidinflammation AT wonheehur roleofhightemperaturerequirementserineproteasea2inrheumatoidinflammation AT seolheeheo roleofhightemperaturerequirementserineproteasea2inrheumatoidinflammation AT saseonglee roleofhightemperaturerequirementserineproteasea2inrheumatoidinflammation AT eunbyeolchoi roleofhightemperaturerequirementserineproteasea2inrheumatoidinflammation AT jaehyungpark roleofhightemperaturerequirementserineproteasea2inrheumatoidinflammation AT youngjaepark roleofhightemperaturerequirementserineproteasea2inrheumatoidinflammation AT wanukkim roleofhightemperaturerequirementserineproteasea2inrheumatoidinflammation AT hyangshukrhim roleofhightemperaturerequirementserineproteasea2inrheumatoidinflammation AT seungahyoo roleofhightemperaturerequirementserineproteasea2inrheumatoidinflammation |