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, and apoptosis or autophagy. However, whether HtrA2 controls inflammation and immune response remains elusive. Results: Here, 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 immune cells counts in the RA SF. Strikingly, in the SF of RA patients, HtrA2 levels were elevated in proportion to synovitis severity and correlated with proinflammation cytokines and chemokines, such as IL-8, IL-6 and CCL2. Of note, HtrA2 was highly expressed in RA synoviums and primary synoviocytes. RA synoviocytes released HtrA2 when stimulated by ER stress inducers. Moreover, knockdown of HtrA2 inhibited IL1β-, TNFα- or LPS-induced release of proinflammatory cytokine and chemokine by RA synoviocytes. Conclusion: HtrA2 is a novel inflammatory mediator and therefore a promising target for developing an anti-inflammation therapy for RA.