Abstract
Traditional treatments, including a variety of thermal therapies have been known since ancient times to provide relief from rheumatoid arthritis (RA) symptoms. However, a general absence of information on how heating affects molecular or immunological targets relevant to RA has limited heat treatment (HT) to the category of treatments known as “alternative therapies”. In this study, we evaluated the effectiveness of mild HT in a collagen-induced arthritis (CIA) model which has been used in many previous studies to evaluate newer pharmacological approaches for the treatment of RA, and tested whether inflammatory immune activity was altered. We also compared the effect of HT to methotrexate, a well characterized pharmacological treatment for RA. CIA mice were treated with either a single HT for several hours or daily 30 minute HT. Disease progression and macrophage infiltration were evaluated. We found that both HT regimens significantly reduced arthritis disease severity and macrophage infiltration into inflamed joints. Surprisingly, HT was as efficient as methotrexate in controlling disease progression. At the molecular level, HT suppressed TNF-α while increasing production of IL-10. We also observed an induction of HSP70 and a reduction in both NF-κB and HIF-1α in inflamed tissues. Additionally, using activated macrophages in vitro, we found that HT reduced production of pro-inflammatory cytokines, an effect which is correlated to induction of HSF-1 and HSP70 and inhibition of NF-κB and STAT activation. Our findings demonstrate a significant therapeutic benefit of HT in controlling arthritis progression in a clinically relevant mouse model, with an efficacy similar to methotrexate. Mechanistically, HT targets highly relevant anti-inflammatory pathways which strongly support its increased study for use in clinical trials for RA.
Highlights
Rheumatoid arthritis (RA) is an autoimmune disease of synovial joints
While heat treatment (HT) had no effect on the onset of disease or on overall incidence (Fig. 1A), it caused a remarkable reduction in disease severity in the remission phase as compared to mice without HT (Fig. 1B)
6 hr HT exerted no effect in the initial inflammatory phase reduced disease severity was evident in the later remission stage of arthritis, in heated mice, this did not quite reach statistical significance
Summary
Rheumatoid arthritis (RA) is an autoimmune disease of synovial joints. Excessive activation of innate immunity is an early event in RA and this appears to initiate synovial inflammation. Macrophages play a central role in the pathogenesis of RA. They accumulate in the synovial membrane and cartilage-pannus junction and secrete pro-inflammatory cytokines and chemokines which activate and recruit other inflammatory cells, driving a chronic cycle of damaging inflammatory responses [1, 2]. TNF-α is the principal pro-inflammatory cytokine produced by activated macrophages which functions synergistically with other cytokines, such as IL-1β, to stimulate synovial fibroblasts and chondrocytes to secrete enzymes that degrade proteoglycans and collagen, leading to tissue destruction. The underlying mechanisms of persistent macrophage activation are not entirely understood, pharmacological targeting of pro-inflammatory cytokine production by these cells has become an important strategy for preventing additional tissue damage and reducing painful symptoms of RA [3]
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