Abstract
Rheumatoid arthritis (RA) is an autoimmune disease that is related to the induction of T helper (Th)17 cells, which secrete interleukin-17, and activation of the signal transducer and activator of transcription (STAT) 3. The expression of high-temperature requirement protein A (HtrA) 2, a serine protease involved in apoptosis, was decreased in RA patients nonresponsive to drug treatment of RA. The aim of this study was to determine whether overexpression of HtrA2 has a therapeutic effect on RA. Th17 differentiation, osteoclastogenesis, and lymphocyte activation are increased in motor neuron degeneration (mnd)2 mice, which lack HtrA2 activity because of a missense mutation (Ser276Cys) in the protease domain of HtrA2. The inhibitor of HtrA2 also increased Th17 differentiation. On the other hand, HtrA2 induced cleavage of STAT3 and overexpression of HtrA2 attenuated CIA in a mouse model. HtrA2 overexpression inhibited plaque development as well as the differentiation of Th17 in ApoE−/− mice after immunization with proteoglycans to induce a hyperlipidemia-based RA animal model. The therapeutic function of HtrA2 in inflammatory diseases is linked with Th17 development and the STAT3 pathway in splenocytes. These results suggest that HtrA2 participates in immunomodulatory activity where the upregulation of HtrA2 may shed light on therapeutic approaches to RA and hyperlipidemia.
Highlights
Rheumatoid arthritis (RA) is a systemic autoimmune disorder involving chronic inflammation
We investigated whether HtrA2 could downregulate the activation of T cells
HtrA2 has been suggested to be a candidate associated with non-response to drug treatments for RA17
Summary
Rheumatoid arthritis (RA) is a systemic autoimmune disorder involving chronic inflammation. Th17 cells exacerbate tissue destruction by inducing chronic inflammation in patients with RA2. Activation of STAT3 induces the production of IL-175,6 and inflammatory CD4+ T cells, such as Th176,7. A considerable proportion of patients with RA fail to respond to drug treatment. Several TNF-αblocker including infliximab do not have therapeutic effects in one-third of patients with RA12. These patients have an increased possibility of not responding to other biologics[13]. It is well documented that gene expression of HtrA2 in peripheral blood mononuclear cells of nonresponders to methotrexate (MTX) is significantly decreased compared with that in responders; HtrA2 is an attractive candidate to test in nonresponders to MTX17
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