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

Thwaites, Ryan S, Unterberger, Sarah, Chamberlain, Giselle, Gray, Henry, Jordan, Kelsey, Davies, Kevin A, Harrison, Neil A and Sacre, Sandra (2021) Expression of sterile-α and armadillo motif in rheumatoid arthritis monocytes correlates with TLR2 induced IL-1β and disease activity. Rheumatology. pp. 1-29. ISSN 1462-0324

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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.

Item Type: Article
Keywords: rheumatoid arthritis, toll-like receptor, interleukin-1, SARM, DAS28
Schools and Departments: Brighton and Sussex Medical School > Clinical and Experimental Medicine
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 10 Feb 2021 08:31
Last Modified: 12 Mar 2021 09:45
URI: http://sro.sussex.ac.uk/id/eprint/97054

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