The upregulation of HtrA2 ameliorates autoimmune arthritis via inhibition of Th17 formation and STAT3 expression (THER3P.974)

Abstract

Abstract HtrA serine peptidase 2 (HtrA2) performs pivotal role in maintaining of the mitochondria homeostasis and involves in cellular stress response such as inflammation. Rheumatoid arthritis (RA) appears to have a basis of mitochondrial dysfunction. To identify the role of HtrA2 in RA, we used a mnd2 mutant mice. We hypothesized that HtrA2 overexpression may reduce immune inflammation and reveal therapeutic effects on RA. We observed that inhibitor and siRNA of HtrA2 in T helper cell (Th) 17 condition increase the mRNA expression of interleukin (IL)-17. On the other hand, the overexpression HtrA2 significantly reduces mRNA level of IL-17 and induces cleavage of STAT3. Moreover, p-STAT3 and lymphocyte activation is promoted in mnd2 mutant mice compared to wild type. HtrA2 overexpression attenuates collagen-induced arthritis (CIA) in mice model. Th17 and osteoclastogenesis are suppressed in CIA mice treated with HtrA2 overexpression. Additionally, HtrA2 overexpression inhibited development of plaque formation and activation of Th17 cell and STAT3 in APOE knock-out mice with proteoglycan immunization for animal model of hyperlipidemia based RA. The therapeutic function of HtrA2 in inflammatory diseases is related with the targeting of Th17 development and STAT3 pathway in splenocytes. These results suggest that HtrA2 takes part in immunomodulatory activity and upregulation of HtrA2 may shed light on therapeutic approaches to inflammatory disorder such as RA and hyperlipidemia.