Expression of sterile-a and armadillo motif in rheumatoid arthritis monocytes correlates with TLR2 induced IL-1ß and disease activity

Objective Cartilage and bone damage in rheumatoid arthritis (RA) are associated with elevated IL-1ß. The effects of IL-1ß can be reduced by biological therapies that target IL-1ß or TNFa. However, the mechanisms responsible for increased IL-1ß and the effect of anti-TNFa have not been fully elucidated. Recently, sterile-a and armadillo motif-containing protein (SARM) was identified as a negative regulator of toll-like receptor (TLR) induced IL-1ß secretion through an interaction with the inflammasome. This study set out to investigate SARM during TLR induced IL-1ß secretion in RA peripheral blood monocytes and in patients commencing anti-TNFa treatment. Methods Monocytes were isolated from RA patients and healthy controls; disease activity was measured by DAS28. IL-1ß secretion was measured by ELISA following TLR1/2, TLR4 and TLR7/8 stimulation. The mRNA expression of SARM, IL-1ß and the components of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome were measured by quantitative PCR. SARM protein expression was measured by western blotting. Results TLR1/2 activation induced elevated IL-1ß in RA monocytes compared with heathy controls (p= 0.0009), which negatively correlated with SARM expression (p?=?0.0086). Lower SARM expression also correlated with higher disease activity (p?=?0.0246). Additionally, patients responding to anti-TNFa treatment demonstrated a rapid upregulation of SARM, which was not observed in non-responders. Conclusion Together, these data highlight a potential contribution from SARM to RA pathophysiology where decreased SARM may lead to elevated IL-1ß associated with RA pathogenesis. Furthermore, the data additionally present a potential mechanism by which TNFa blockade can modify IL-1ß secretion.