Plenary Poster 29th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting 2019

The role of NLRP3 inflammasome activation in joint inflammation and destruction in rheumatoid arthritis: novel therapeutic approaches with TAK1 inhibition. (#92)

Hirofumi Tenshin 1 , Jumpei Teramachi 2 , Masahiro Hiasa 1 , Asuka Oda 3 , Mohannad Ashtar 1 , Kotaro Tanimoto 1 , So Shimizu 1 , Takeshi Harada 3 , Masahiro Oura 3 , Kimiko Sogabe 3 , Itsuro Endo 3 , Eiji Tanaka 1 , Toshio Matsumoto 4 , Masahiro Abe 3
  1. Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
  2. Department of Tissue Regeneration, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
  3. Department of hematology, endocrinology and metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
  4. Fujii Memorial Institute of Medical Sciences, Tokushima University, Tokushima, Japan

Although aberrant NLRP3 inflammasome activation and thereby IL-1β production has been considered to contribute to joint inflammation in rheumatoid arthritis (RA), the causative roles of NLRP3 inflammasome activation in inflammation and bone destruction in RA joints remain elusive. TGF-β activated kinase-1 (TAK1) mediates a wide range of biological processes associated with inflammation. Here, we aimed to clarify the roles of TAK1 in NLRP3 inflammasome activation and thereby inflammation and bone destruction in RA, using mice with collagen-induced arthritis (CIA). Treatment with the TAK1 inhibitor LLZ1640-2 substantially alleviated pain as well as inflammatory scores in joints in CIA mice. Histological analyses showed that LLZ suppressed synovial hypertrophy and pannus formation, and reduced osteoclast numbers on bone surface in their joints. Although NRLP3 as well as RANK ligand expression in synovial tissues and serum IL-1β levels were increased in the CIA mice, the TAK1 inhibition markedly suppressed these changes. LLZ or TAK1 gene silencing almost completely suppressed NLRP3 and pro-IL-1β induction while subsequent NLRP3 inflammasome activation and IL-1β production by ATP in bone marrow macrophages (BMMs) upon priming with lipopolysaccharide, a TLR4 agonist. Besides suppression of IL-1β production by BMMs, the TAK1 inhibition downregulated IL-1β-induced RANKL mRNA expression in synovial fibroblasts, and suppressed osteoclast differentiation from BMMs in cocultures with the synovial fibroblasts. Furthermore, RANK ligand as well as TNF-α immediately induced phosphorylation of TAK1 in BMMs or RAW264.7 preosteoclastic cells; however, LLZ abolished the TAK1 phosphorylation and suppressed their osteoclast differentiation by RANK ligand. From these results, TAK1 inhibition can effectively block NLRP3 inflammasome-mediated inflammation, and RANK ligand expression and osteoclastic bone resorption. Therefore, TAK1 inhibition may become a novel treatment strategy targeting inflammasome priming and activation while suppressing NF-κB and the MAP kinase to effectively alleviate inflammation as well as bone destruction in RA.