TLR1/2 and 5 induce elevated cytokine levels from rheumatoid arthritis monocytes independent of ACPA or RF autoantibody status.

Ryan S Thwaites,Karen Walker-Bone,Giselle Chamberlain,Sarah Unterberger,Kevin A Davies,Sandra Sacre

doi:10.1093/rheumatology/keaa220

Ryan S Thwaites, Karen Walker-Bone + Show 4 more

Open Access

https://doi.org/10.1093/rheumatology/keaa220

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Abstract

ObjectiveRA is an autoimmune inflammatory joint disease. Both RF and ACPA are associated with more progressive disease and higher levels of systemic inflammation. Monocyte activation of toll-like receptors (TLRs) by endogenous ligands is a potential source of increased production of systemic cytokines. RA monocytes have elevated TLRs, some of which are associated with the disease activity score using 28 joints (DAS28). The aim of this study was to measure TLR-induced cytokine production from monocytes, stratified by autoantibody status, to assess if their capacity to induce cytokines is related to autoantibody status or DAS28.MethodsPeripheral blood monocytes isolated from RA patients and healthy controls were stimulated with TLR1/2, TLR2/6, TLR4, TLR5, TLR7, TLR8 and TLR9 ligands for 18 h before measuring IL-6, TNFα and IL-10. Serum was used to confirm the autoantibody status. Cytokine levels were compared with RF, ACPA and DAS28.ResultsRA monocytes demonstrated significantly increased IL-6 and TNFα upon TLR1/2 stimulation and IL-6 and IL-10 upon TLR5 activation. TLR7 and TLR9 activation did not induce cytokines and no significant differences were observed between RA and healthy control monocytes upon TLR2/6, TLR4 or TLR8 activation. When stratified by ACPA or RF status there were no correlations between autoantibody status and elevated cytokine levels. However, TLR1/2-induced IL-6 did correlate with DAS28.ConclusionsElevated TLR-induced cytokines in RA monocytes were not related to ACPA or RF status. However, TLR1/2-induced IL-6 was associated with disease activity.

Highlights

RA is a chronic autoimmune disease, characterized by inflammation of the synovial joints and the production of autoantibodies
Peripheral blood monocytes isolated from RA patients and healthy controls were stimulated with TLR1/ 2, TLR2/6, TLR4, TLR5, TLR7, TLR8 and TLR9 ligands for 18 h before measuring IL-6, TNFa and IL-10
None of the cytokines measured after TLR5 activation significantly correlated with disease activity score using 28 joints (DAS28) (Fig. 2D). As both autoantibody status and toll-like receptors (TLRs) have been associated with elevated inflammation and disease severity in RA, this study investigated whether there was a link between elevated levels of TLR-induced cytokines in peripheral blood CD14þ monocytes and RF or ACPA status

Summary

Introduction

RA is a chronic autoimmune disease, characterized by inflammation of the synovial joints and the production of autoantibodies. RF is not specific for RA, whereas ACPA are highly specific, often detectable many years prior to disease onset. Both ACPA and RF are associated with a more severe clinical prognosis alongside increased systemic inflammation, especially when. The majority of studies have focused on TLRs expressed by cells within the inflamed joints, TLR activation of circulating monocytes may have a role in joint inflammation through migration and differentiation to macrophages and osteoclasts and they may facilitate the systemic inflammation associated with RA co-morbidities such as cardiovascular disease

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