Ligation of TLR7 by rheumatoid arthritis synovial fluid single strand RNA induces transcription of TNFα in monocytes.
OBJECTIVE
The aim of the study was to characterise the expression, regulation and pathogenic role of toll-like receptor 7 (TLR7) and TLR8 in rheumatoid arthritis (RA).


METHODS
Expression of TLR7 and TLR8 was demonstrated in RA, osteoarthritis (OA) and normal (NL) synovial tissues (STs) employing immunohistochemistry. The authors next examined the mechanism by which TLR7 and TLR8 ligation mediates proinflammatory response by Western blot analysis and ELISA. Expression of TLR7 and TLR8 in RA monocytes was correlated to disease activity score (DAS28) and tumour necrosis factor α (TNFα) levels. Further, the effect of TLR7 ligation in RA monocytes was determined on synovial fluid (SF)-mediated TNFα transcription.


RESULTS
TLR7/8 are predominately expressed in RA ST lining and sublining macrophages. The authors show that NF-κB and/or PI3K pathways are essential for TLR7/8 induction of proinflammatory factors in RA peripheral blood (PB)-differentiated macrophages. Expression of TLR7 in RA monocytes shows a strong correlation with DAS28 and TNFα levels. By contrast, expression of TLR8 in these cells does not correlate with DAS28, TLR7 or TNFα levels. The authors further demonstrate that RNA from RA SF, but not RA or NL plasma, could modulate TNFα transcription from RA monocytes that can be downregulated by antagonising TLR7 ligation or degradation of single stand (ss) RNA. Thus, ssRNA present in RA SF may function as a potential endogenous ligand for TLR7.


CONCLUSIONS
These results suggest that expression of TLR7, but not TLR8, may be a predictor for RA disease activity and anti-TNFα responsiveness, and targeting TLR7 may suppress chronic progression of RA.
Department of Medicine, Division of Rheumatology, University of Illinois at Chicago, 835 S Wolcott Ave., E807-E809 MSB, Chicago, Illinois 60612, USA.
Nathan D
ND
Chamberlain
Seung-jae
SJ
Kim
Olga M
OM
Vila
Michael V
MV
Volin
Suncica
S
Volkov
Richard M
RM
Pope
Shiva
S
Arami
Arthur M
AM
Mandelin
Shiva
S
Shahrara
D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism*; D012313:RNA / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013582:Synovial Fluid / Q000378:metabolism*; D051199:Toll-Like Receptor 7 / Q000096:biosynthesis*; D051200:Toll-Like Receptor 8 / Q000096:biosynthesis*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D014409:Tumor Necrosis Factor-alpha; D012313:RNA