Celastrol Exerts Cardioprotective Effect in Rheumatoid Arthritis by Inhibiting TLR2/HMGB1 Signaling Pathway-Mediated Autophagy

Abstract

<b><i>Objective:</i></b> Rheumatoid arthritis (RA) is a kind of chronic inflammatory disease characterized by the release of inflammatory cytokines and cardiomyocyte apoptosis, which lead to increased riskfor heart diseases. This study aims to explore the possible effect and mechanism of Celastrol on RA induced cardiac impairments in rats. <b><i>Methods:</i></b> Collagen induced RA wistar rat models (CIA) were established for the measurement on secondary foot swelling degree, polyarthritis index score, spleen and thymus index. Pathological morphology was observed using H&E staining. Heart fibrosis was measured after Sirius red staining, while cell apoptosis was determined by TUNEL staining. For in vitro experiments, rat cardiomyocytes were isolated to determine the inflammatory cytokine secretion and cell apoptosis using ELISA and flow cytometry, respectively. Protein expressions of related index and autophagy were detected by Western blot and immunofluorescence. <b><i>Results:</i></b> CIA rat model was successfully established and characterized by severe secondary foot swelling degree, and increased polyarthritis index score and spleen and thymus index. Synovial hyperplasia, disordered cardiomyocytes, cell infiltration and fibrosis were also observed in CIA rat model. Compared with CIA model, Celastrol treatment could suppress the release of inflammatory cytokines, including TNF-α, IL-6, IL-1β, as well as inhibiting the expressions of Bax, cleaved caspase3, collagen I, collagen III and α-SMA. In addition to that, Celastrol treatment can attenuate cell apoptosis and fibrosis of cardiomyocytes and elevate Bcl-2 expression. RA induced cell autophagy can be suppressed by Celastrol through inhibiting the activation of TLR2/HMGB1 signal pathway. <b><i>Conclusion:</i></b> Celastrol can regulate TLR2/HMGB1 signal pathway to suppress autophagy and therefore exert cardioprotective effect in RA.

Celastrol ameliorates osteoarthritis via regulating TLR2/NF-κB signaling pathway

“…A related study found that celastrol could promote autophagy in vitro and in vivo to protect chondrocyte ( Feng et al, 2020 ). Although celatrol has a powerful anti-inflammatory effect, few studies have examined whether such effects are brought out by inhibiting innate immunity, especially TLR2, which has only been reported in multiple sclerosis and RA ( Abdin and Hasby, 2014 ; Lu et al, 2021 ). Furthermore, whether celastrol can regulate TLRs-mediated innate immunity in OA has never been investigated to the best of our knowledge.…”

“…As a valuable inhibitor of NF-κB signaling pathway, celastrol shows anti-inflammatory and bone protective effects in the adjuvant-induced arthritis model ( Cascao et al, 2020 ). Moreover, it has been found that celastrol plays a cardioprotective role in rheumatoid arthritis by inhibiting autophagy mediated by TLR2/HMGB1 signaling pathway ( Lu et al, 2021 ). Compared with autoimmune arthritis, OA is mainly characterized by chronic, relatively low-grade inflammation.…”

lncRNA HOTAIR Inhibition by Regulating HMGB1/ROS/NF-κB Signal Pathway Promotes the Recovery of Spinal Cord Function

“…The inflammatory role of extracellular HMGB1 has attracted extensive attention both nationally and internationally [16]. Follow-up studies have shown that HMGB1, which enters the extracellular medium, can act as an important inflammatory mediator in the development of various diseases, such as sepsis, arthritis, and ischemiareperfusion injury [17][18][19]. In SCII, HMGB1 can promote oxidative stress and inflammatory damage [20].…”

Old and new damage‐associated molecular patterns (DAMPs) in autoimmune diseases

“…Furthermore, HMGB1‐elevated secretions have been speculated to trigger dendritic cell and macrophage antigen‐presenting abilities by upregulating major histocompatibility complex II (MHC II), CD83, CD80, and CD86 expression on macrophage surfaces. Consequently, this leads to induction of dendritic cell maturation, activation of T‐helper cells and B lymphocytes, and differentiation of proliferating CD4 + T cells to Th2 and Th17 cells 27–32 . Although BD patients have reportedly elevated the expression levels of HMGB1 compared with healthy controls, controversy about the correlation between HMGB‐1 expression and the Behçet's disease current activity form and Behçet's syndrome activity score 33,34 .…”