TGF‐β‐activated kinase‐1 inhibitor LL‐Z1640‐2 reduces joint inflammation and bone destruction in mouse models of rheumatoid arthritis by inhibiting NLRP3 inflammasome, TACE, TNF‐α and RANKL expression

Abstract

Objectives. Aberrant NLRP3 inflammasome activation has been demonstrated in rheumatoid arthritis (RA), which may contribute to debilitating inflammation and bone destruction. Here, we explored the efficacy of the potent TGF-b-activated kinase-1 (TAK1) inhibitor LL-Z1640-2 (LLZ) on joint inflammation and bone destruction in collagen-induced arthritis (CIA). Methods. LL-Z1640-2 was administered every other day in CIA mice. Clinical and histological evaluation was performed. Priming and activation of NLRP3 inflammasome and osteoclastogenic activity were assessed. Results. NLRP3 inflammasome formation was observed in synovial macrophages and osteoclasts (OCs) in CIA mice. TACE and RANKL were also overexpressed in synovial macrophages and fibroblasts, respectively, in the CIA joints. Treatment with LLZ mitigated all the above changes. As a result, LLZ markedly suppressed synovial hypertrophy and pannus formation to alleviate pain and inflammation in CIA mice. LLZ could block the priming and activation of NLRP3 inflammasome in RAW264.7 macrophage cell line, primary bone marrow macrophages and OCs upon treatment with LPS followed by ATP, thereby suppressing their IL-1b production. LLZ also suppressed LPS-induced production of TACE and TNF-a in bone marrow macrophages and abolished IL-1binduced production of MMP-3, IL-6 and RANKL in synovial fibroblasts. In addition, LLZ directly inhibits RANKL-mediated OC formation and activation. Conclusion. TAK1 inhibition with LLZ

Wedelolactone ameliorates synovial inflammation and cardiac complications in a murine model of collagen-induced arthritis by inhibiting NF-κB/NLRP3 inflammasome activation

“…In line with previous findings in different experimental models of inflammation, our study demonstrated that Wed blocked the activation of NLRP3 inflammasome and synovial inflammation in CIA mice. Stimulation of IL-1β production by NLRP3 is thought to induce the production of RANKL, matrix metalloproteinase 3 (MMP-3), and downstream inflammatory cytokines such as IL-6 [45]. Our findings collectively imply that Wed may prevent RA development via inhibiting the NLRP3 inflammasome activation.…”

Role of NLRP3 Inflammasome in Rheumatoid Arthritis

“…LLZ showed superior therapeutic efficacy against RA in preclinical trials. In CIA mice, LLZ was observed to significantly prevent the formation and activation of NLRP3 inflammasome in synovial macrophages and osteoclasts ( 125 ). A recently identified novel compound 59 known as J114 was shown to interfere with NLRP3-ASC interaction and potently suppress ASC oligomerization during NLRP3 activation.…”

Therapeutic efficacy of the resorcylic acid lactone LL‐Z1640‐2 for adult T‐cell leukaemia/lymphoma

“…Although the primary target of LL-Z1640-2 is TAK1, LL-Z1640-2 has been shown to exert off-target effects, including inhibition of MEK1/2 and MKK3/6 [10]. The inhibition of MKK3/6-p38 MAPK signalling together with TAK1 by LL-Z1640-2 has been shown to contribute to the anti-inflammatory effects of LL-Z1640-2 in rheumatoid arthritis [11]. Therefore, we examined the effects of LL-Z1640-2 on p38 MAPK-mediated signalling.…”

“…Furthermore, LL‐Z1640‐2 was shown to be the most effective inhibitor of the activation of synovial fibroblasts in rheumatoid arthritis [10]. We previously reported that LL‐Z1640‐2 effectively suppressed inflammation and joint destruction in mice with collagen‐induced arthritis as a model of rheumatoid arthritis [11]. Moreover, the therapeutic efficacy of TAK1 inhibition has been examined in preclinical models of various cancers, including mantle cell lymphoma [12], breast cancer [13], and ovarian cancer [14].…”