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 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.

HTRA2/OMI-Mediated Mitochondrial Quality Control Alters Macrophage Polarization Affecting Systemic Chronic Inflammation

“…However, its therapeutic utility is speculative and further studies are needed to fully grasp its role. The location of elevated HtrA2/Omi varies in different inflammatory diseases, with higher concentrations of HtrA2 in rheumatoid arthritis (RA) synovial fluid (SF) than in osteoarthritis (OA) SF, which correlates with the number of immune cells in RA SF, and with the finding that treatment of RA FLS with an endoplasmic reticulum stress inducer resulted in the release of HtrA2/Omi from the mitochondria into the extracellular space [28]. In addition, HtrA2/Omi was released from mitochondria to the cytoplasm in pneumonia [18].…”

“…Notably, HtrA2/Omi is involved in the development of several SCIs including rheumatoid arthritis (RA) and neuroinflammation. Jeong et al showed that during endoplasmic reticulum stress-induced apoptosis, synoviocytes release HtrA2 into the synovial lumen of the RA, which is a key regulator of the production of inflammatory cytokines [28]. HtrA2 contributes to the pathogenesis of autoimmune arthritis through the differentiation of Th17 cells by STAT3 [29].…”

“…Under apoptotic signaling, HtrA2/Omi is released from the mitochondria into the cytoplasmic lysate and is involved in disease progression in neurodegeneration and rheumatoid arthritis [27]. In addition, in endoplasmic reticulum stress-induced RA-FLS, HtrA2 is released from mitochondria to the extracellular space [28]. It suggests that long-term exposure of macrophages to oxidative stress and heat stress within the SCI response releases HtrA2/Omi from the mitochondrial membrane interstitial space to the mitochondrial matrix, cytoplasm, and extracellularly, which ultimately leads to a decrease in mitochondrial membrane interstitial HtrA2/Omi.…”

Implications of siRNA Therapy in Bone Health: Silencing Communicates

“…A cationic liposome-transfecting agent, Lipofectamine TM 3000, was fused with high-temperature serine protease A (HtrA2) siRNA into the fibroblast-like synoviocytes (FLSs) derived from individuals suffering from rheumatoid arthritis and osteoarthritis with articular replacement surgery in vitro. Suppression of the HtrA2 gene along with inhibition of expression of various pro-inflammatory biomarkers like IL-1β, TNF-α, CCL-2, IL-6, and IL-8 was observed without exhibiting any cytotoxicity in the FLS cells in vitro [91]. A lipofectamine RNAiMAX reagent was employed to encapsulate siRNAs to silence mammalian targets of rapamycin complexes 1 and 2 (mTORC1 and mTORC2), regulatory-associated proteins of mTOR complexes 1 and 2 (RAPTOR), and rapamycin-insensitive companions of mTOR (RICTOR) of the mTOR signaling pathway.…”