Expression of sterile-α and armadillo motif containing protein (SARM) in rheumatoid arthritis monocytes correlates with TLR2-induced IL-1β and disease activity

Abstract

Objective Cartilage and bone damage in rheumatoid arthritis (RA) are associated with elevated IL-1β. The effects of IL-1β can be reduced by biological therapies that target IL-1β or TNFα. However, the mechanisms responsible for increased IL-1β and the effect of anti-TNFα have not been fully elucidated. Recently, sterile-α and armadillo motif-containing protein (SARM) was identified as a negative regulator of toll-like receptor (TLR) induced IL-1β secretion through an interaction with the inflammasome. This study set out to investigate SARM during TLR induced IL-1β secretion in RA peripheral blood monocytes and in patients commencing anti-TNFα treatment. Methods Monocytes were isolated from RA patients and healthy controls; disease activity was measured by DAS28. IL-1β secretion was measured by ELISA following TLR1/2, TLR4 and TLR7/8 stimulation. The mRNA expression of SARM, IL-1β 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-1β 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-TNFα 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-1β associated with RA pathogenesis. Furthermore, the data additionally present a potential mechanism by which TNFα blockade can modify IL-1β secretion.

Contribution of Toll-Like Receptors and the NLRP3 Inflammasome in Rheumatoid Arthritis Pathophysiology

“…39 Additionally, RA patient monocytes produce higher levels of cytokines compared to healthy donors upon activation of TLR1/2 and TLR2/6. 33,40,41 However, despite increased TLR1 in seropositive RA, we found no association of RF or ACPA status with the level of TLR1/2 cytokine production; although TLR1/2 induced IL-6 did correlate with DAS28. 36,40 TLR2 activation of RA FLS also strongly induces Receptor activator of nuclear factor kappa-Β ligand (RANKL) promoting osteoclastogenesis and TLR2 activated M2 macrophages derived from RA patient monocytes exhibit an impaired anti-inflammatory activity.…”

“… 74 Pro-inflammatory cytokine production Activation of TLR1/2 and TLR2/6. 33 , 40 , 41 TLR4 activated RA SF macrophages 65 and TLR5 activated monocytes induce elevated cytokines. 40 Inhibition of TLR2 45 and TLR8 83–85 reduces spontaneous cytokine release from RA synovial tissue.…”

“…Activation of TLR1/2 and TLR2/6. 33,40,41 TLR4 activated RA SF macrophages 65 and TLR5 activated monocytes induce elevated cytokines. 40 Inhibition of TLR2 45 and TLR8 [83][84][85]…”

“…Furthermore, RA patients responsive to anti-TNF therapy then displayed a transient increase in the expression of SARM in their monocytes, which was not observed in non-responders. 116 Further compounding effects on NLRP3 activation have been suggested in the presence of key RA cytokines. TNF can prime cells such as FLS to upregulate NLRP3 and pro-IL-1β.…”

“…Furthermore, RA patients responsive to anti-TNF therapy then displayed a transient increase in the expression of SARM in their monocytes, which was not observed in non-responders. 116 …”