Role of high-temperature requirement serine protease A 2 in rheumatoid inflammation.
Humans
Arthritis, Rheumatoid
/ metabolism
Cells, Cultured
Chemokines
/ metabolism
Cytokines
/ metabolism
Fibroblasts
/ metabolism
Inflammation
/ pathology
Interleukin-6
/ metabolism
Interleukin-8
/ metabolism
Serine Endopeptidases
/ metabolism
Serine Proteases
/ metabolism
Synovial Membrane
/ metabolism
Synoviocytes
/ metabolism
Temperature
Tumor Necrosis Factor-alpha
/ metabolism
Fibroblast-like synoviocytes
High-temperature requirement serine protease A
Inflammation
Rheumatoid arthritis
Journal
Arthritis research & therapy
ISSN: 1478-6362
Titre abrégé: Arthritis Res Ther
Pays: England
ID NLM: 101154438
Informations de publication
Date de publication:
07 06 2023
07 06 2023
Historique:
received:
26
12
2022
accepted:
01
06
2023
medline:
9
6
2023
pubmed:
8
6
2023
entrez:
7
6
2023
Statut:
epublish
Résumé
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. 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. 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. HtrA2 is a novel inflammatory mediator and a potential target for the development of an anti-inflammation therapy for RA.
Sections du résumé
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.
Identifiants
pubmed: 37287073
doi: 10.1186/s13075-023-03081-z
pii: 10.1186/s13075-023-03081-z
pmc: PMC10246393
doi:
Substances chimiques
Chemokines
0
Cytokines
0
Interleukin-6
0
Interleukin-8
0
Serine Endopeptidases
EC 3.4.21.-
Serine Proteases
EC 3.4.-
Tumor Necrosis Factor-alpha
0
HTRA2 protein, human
EC 3.4.21.108
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
96Informations de copyright
© 2023. The Author(s).
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