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

References

• Smolen JS, Aletaha D, Barton A, et al. Rheumatoid arthritis. Nat Rev Dis Primers. 2018;4:18001.
   PubMed Web of Science ®Google Scholar
• Malmstrom V, Catrina AI, Klareskog L. The immunopathogenesis of seropositive rheumatoid arthritis: from triggering to targeting. Nat Rev Immunol. 2017;17(1):60–75. doi:10.1038/nri.2016.124
   PubMed Web of Science ®Google Scholar
• Frisell T, Holmqvist M, Källberg H, Klareskog L, Alfredsson L, Askling J. Familial risks and heritability of rheumatoid arthritis: role of rheumatoid factor/anti-citrullinated protein antibody status, number and type of affected relatives, sex, and age. Arthritis Rheum. 2013;65(11):2773–2782. doi:10.1002/art.38097
   PubMed Web of Science ®Google Scholar
• Okada Y, Eyre S, Suzuki A, Kochi Y, Yamamoto K. Genetics of rheumatoid arthritis: 2018 status. Ann Rheum Dis. 2019;78(4):446–453. doi:10.1136/annrheumdis-2018-213678
   PubMed Web of Science ®Google Scholar
• Khandpur R, Carmona-Rivera C, Vivekanandan-Giri A, et al. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci Transl Med. 2013;5(178):178ra140. doi:10.1126/scitranslmed.3005580
   Web of Science ®Google Scholar
• Law ST, Taylor PC. Role of biological agents in treatment of rheumatoid arthritis. Pharmacol Res. 2019;150:104497. doi:10.1016/j.phrs.2019.104497
   PubMed Web of Science ®Google Scholar
• Taylor PC. Clinical efficacy of launched JAK inhibitors in rheumatoid arthritis. Rheumatology. 2019;58(Suppl 1):i17–i26. doi:10.1093/rheumatology/key225
   PubMed Web of Science ®Google Scholar
• Kawasaki T, Kawai T. Toll-like receptor signaling pathways. Front Immunol. 2014;5:461. doi:10.3389/fimmu.2014.00461
   PubMed Web of Science ®Google Scholar
• Lee SM, Yip TF, Yan S, et al. Recognition of double-stranded RNA and regulation of interferon pathway by toll-like receptor 10. Front Immunol. 2018;9:516. doi:10.3389/fimmu.2018.00516
   PubMed Web of Science ®Google Scholar
• Jenkins KA, Mansell A. TIR-containing adaptors in toll-like receptor signalling. Cytokine. 2010;49(3):237–244. doi:10.1016/j.cyto.2009.01.009
   PubMed Web of Science ®Google Scholar
• Shevlin E, Miggin SM, Wang T. The TIR-domain containing adaptor TRAM is required for TLR7 mediated RANTES production. PLoS One. 2014;9(9):e107141. doi:10.1371/journal.pone.0107141
   Web of Science ®Google Scholar
• Leszczyńska E, Makuch E, Mitkiewicz M, et al. Absence of Mal/TIRAP results in abrogated imidazoquinolinones-dependent activation of IRF7 and suppressed IFNβ and IFN-I activated gene production. Int J Mol Sci. 2020;21(23):8925. doi:10.3390/ijms21238925
   Web of Science ®Google Scholar
• Sacre SM, Lundberg AM, Andreakos E, Taylor C, Feldmann M, Foxwell BM. Selective use of TRAM in lipopolysaccharide (LPS) and lipoteichoic acid (LTA) induced NF-kappaB activation and cytokine production in primary human cells: TRAM is an adaptor for LPS and LTA signaling. J Immunol. 2007;178(4):2148–2154. doi:10.4049/jimmunol.178.4.2148
   Web of Science ®Google Scholar
• Hazuda DJ, Lee JC, Young PR. The kinetics of interleukin 1 secretion from activated monocytes. Differences between interleukin 1α and interleukin 1β. J Biol Chem. 1988;263(17):8473–8479. doi:10.1016/S0021-9258(18)68502-3
   Web of Science ®Google Scholar
• Martinon F, Burns K, Tschopp J. The Inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol Cell. 2002;10(2):417–426. doi:10.1016/S1097-2765(02)00599-3
   PubMed Web of Science ®Google Scholar
• Martinon F, Tschopp J. NLRs join TLRs as innate sensors of pathogens. Trends Immunol. 2005;26(8):447–454. doi:10.1016/j.it.2005.06.004
   PubMed Web of Science ®Google Scholar
• Fernandes-Alnemri T, Wu J, Yu JW, et al. The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation. Cell Death Differ. 2007;14(9):1590–1604. doi:10.1038/sj.cdd.4402194
   PubMed Web of Science ®Google Scholar
• He W-T, Wan H, Hu L, et al. Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion. Cell Res. 2015;25(12):1285–1298. doi:10.1038/cr.2015.139
   PubMed Web of Science ®Google Scholar
• Liu X, Zhang Z, Ruan J, et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature. 2016;535(7610):153–158. doi:10.1038/nature18629
   PubMed Web of Science ®Google Scholar
• Bauernfeind FG, Horvath G, Stutz A, et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol. 2009;183(2):787–791. doi:10.4049/jimmunol.0901363
   PubMed Web of Science ®Google Scholar
• He Y, Franchi L, Núñez G. TLR agonists stimulate Nlrp3-dependent IL-1β production independently of the purinergic P2X7 receptor in dendritic cells and in vivo. J Immunol. 2013;190(1):334–339. doi:10.4049/jimmunol.1202737
   PubMed Web of Science ®Google Scholar
• Dietsch GN, Lu H, Yang Y, et al. Coordinated activation of toll-like receptor 8 (TLR8) and NLRP3 by the TLR8 agonist, VTX-2337, ignites tumoricidal natural killer cell activity. PLoS One. 2016;11(2):e0148764–e0148764. doi:10.1371/journal.pone.0148764
   Web of Science ®Google Scholar
• Fernandes-Alnemri T, Kang S, Anderson C, Sagara J, Fitzgerald KA, Alnemri ES. Cutting edge: TLR signaling licenses IRAK1 for rapid activation of the NLRP3 inflammasome. J Immunol. 2013;191(8):3995–3999. doi:10.4049/jimmunol.1301681
   PubMed Web of Science ®Google Scholar
• Franchi L, Eigenbrod T, Núñez G. Cutting edge: TNF-alpha mediates sensitization to ATP and silica via the NLRP3 inflammasome in the absence of microbial stimulation. J Immunol. 2009;183(2):792–796. doi:10.4049/jimmunol.0900173
   PubMed Web of Science ®Google Scholar
• Kelley N, Jeltema D, Duan Y, He Y. The NLRP3 inflammasome: an overview of mechanisms of activation and regulation. Int J Mol Sci. 2019;20(13):3328. doi:10.3390/ijms20133328
   PubMed Web of Science ®Google Scholar
• Gaidt Moritz M, Ebert TS, Chauhan D, et al. Human monocytes engage an alternative inflammasome pathway. Immunity. 2016;44(4):833–846. doi:10.1016/j.immuni.2016.01.012
   Web of Science ®Google Scholar
• Sandall CF, MacDonald JA. Effects of phosphorylation on the NLRP3 inflammasome. Arch Biochem Biophys. 2019;670:43–57. doi:10.1016/j.abb.2019.02.020
   Web of Science ®Google Scholar
• Shao L, Liu Y, Wang W, et al. SUMO1 SUMOylates and SENP3 deSUMOylates NLRP3 to orchestrate the inflammasome activation. FASEB J. 2020;34(1):1497–1515. doi:10.1096/fj.201901653R
   Web of Science ®Google Scholar
• Mishra BB, Rathinam VA, Martens GW, et al. Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome-dependent processing of IL-1β. Nat Immunol. 2013;14(1):52–60. doi:10.1038/ni.2474
   PubMed Web of Science ®Google Scholar
• Lopez-Castejon G. Control of the inflammasome by the ubiquitin system. Febs j. 2020;287(1):11–26. doi:10.1111/febs.15118
   PubMed Web of Science ®Google Scholar
• Carty M, Kearney J, Shanahan KA, et al. Cell survival and cytokine release after inflammasome activation is regulated by the toll-IL-1R protein SARM. Immunity. 2019;50(6):1412–1424.e1416. doi:10.1016/j.immuni.2019.04.005
   PubMed Web of Science ®Google Scholar
• Sacre SM, Andreakos E, Kiriakidis S, et al. The toll-like receptor adaptor proteins MyD88 and Mal/TIRAP contribute to the inflammatory and destructive processes in a human model of rheumatoid arthritis. Am J Pathol. 2007;170(2):518–525. doi:10.2353/ajpath.2007.060657
   PubMed Web of Science ®Google Scholar
• Lacerte P, Brunet A, Egarnes B, Duchene B, Brown JP, Gosselin J. Overexpression of TLR2 and TLR9 on monocyte subsets of active rheumatoid arthritis patients contributes to enhance responsiveness to TLR agonists. Arthritis Res Ther. 2016;18:10. doi:10.1186/s13075-015-0901-1
   PubMed Web of Science ®Google Scholar
• Iwahashi M, Yamamura M, Aita T, et al. Expression of toll-like receptor 2 on CD16+ blood monocytes and synovial tissue macrophages in rheumatoid arthritis. Arthritis Rheum. 2004;50(5):1457–1467. doi:10.1002/art.20219
   PubMed Web of Science ®Google Scholar
• Clanchy FIL, Borghese F, Bystrom J, et al. TLR expression profiles are a function of disease status in rheumatoid arthritis and experimental arthritis. J Autoimmun. 2021;118:102597. doi:10.1016/j.jaut.2021.102597
   Web of Science ®Google Scholar
• Abdelwahab A, Palosaari S, Abdelwahab SA, et al. Differential synovial tissue expression of TLRs in seropositive and seronegative rheumatoid arthritis: a preliminary report. Autoimmunity. 2021;54(1):23–34. doi:10.1080/08916934.2020.1864729
   PubMed Web of Science ®Google Scholar
• Yu M, Wang H, Ding A, et al. HMGB1 signals through toll-like receptor (TLR) 4 and TLR2. Shock. 2006;26(2):174–179. doi:10.1097/01.shk.0000225404.51320.82
   PubMed Web of Science ®Google Scholar
• He Z, Shotorbani SS, Jiao Z, et al. HMGB1 promotes the differentiation of Th17 via up-regulating TLR2 and IL-23 of CD14+ monocytes from patients with rheumatoid arthritis. Scand J Immunol. 2012;76(5):483–490. doi:10.1111/j.1365-3083.2012.02759.x
   Web of Science ®Google Scholar
• Huang QQ, Sobkoviak R, Jockheck-Clark AR, et al. Heat shock protein 96 is elevated in rheumatoid arthritis and activates macrophages primarily via TLR2 signaling. J Immunol. 2009;182(8):4965–4973. doi:10.4049/jimmunol.0801563
   PubMed Web of Science ®Google Scholar
• Thwaites RS, Unterberger S, Chamberlain G, Walker-Bone K, Davies KA, Sacre S. TLR1/2 and 5 induce elevated cytokine levels from rheumatoid arthritis monocytes independent of ACPA or RF autoantibody status. Rheumatology. 2020;59(11):3533–3539. doi:10.1093/rheumatology/keaa220
   Web of Science ®Google Scholar
• Thwaites RS, Unterberger S, Chamberlain G, et al. Expression of sterile-α and armadillo motif in rheumatoid arthritis monocytes correlates with TLR2 induced IL-1β and disease activity. Rheumatology. 2021. doi:10.1093/rheumatology/keab162
   Web of Science ®Google Scholar
• Kim K-W, Cho M-L, Lee S-H, et al. Human rheumatoid synovial fibroblasts promote osteoclastogenic activity by activating RANKL via TLR-2 and TLR-4 activation. Immunol Lett. 2007;110(1):54–64. doi:10.1016/j.imlet.2007.03.004
   PubMed Web of Science ®Google Scholar
• Quero L, Hanser E, Manigold T, Tiaden AN, Kyburz D. TLR2 stimulation impairs anti-inflammatory activity of M2-like macrophages, generating a chimeric M1/M2 phenotype. Arthritis Res Ther. 2017;19(1):245. doi:10.1186/s13075-017-1447-1
   PubMed Web of Science ®Google Scholar
• McGarry T, Veale DJ, Gao W, Orr C, Fearon U, Connolly M. Toll-like receptor 2 (TLR2) induces migration and invasive mechanisms in rheumatoid arthritis. Arthritis Res Ther. 2015;17(1):153. doi:10.1186/s13075-015-0664-8
   Web of Science ®Google Scholar
• Ultaigh SN, Saber TP, McCormick J, et al. Blockade of toll-like receptor 2 prevents spontaneous cytokine release from rheumatoid arthritis ex vivo synovial explant cultures. Arthritis Res Ther. 2011;13(1):R33. doi:10.1186/ar3261
   Web of Science ®Google Scholar
• Zhu W, Meng L, Jiang C, et al. Induction of toll-like receptor 2 positive antigen-presenting cells in spleen of pristane-induced arthritis in rats. Mol Biol Rep. 2012;39(4):3667–3673. doi:10.1007/s11033-011-1141-3
   Web of Science ®Google Scholar
• Roome T, Aziz S, Razzak A, et al. Opuntioside, opuntiol and its metallic nanoparticles attenuate adjuvant-induced arthritis: novel suppressors of toll-like receptors −2 and −4. Biomed Pharmacother. 2019;112:108624. doi:10.1016/j.biopha.2019.108624
   Web of Science ®Google Scholar
• Bai L, Bai Y, Yang Y, et al. Baicalin alleviates collagen-induced arthritis and suppresses TLR2/MYD88/NF‑κB p65 signaling in rats and HFLS‑RAs. Mol Med Rep. 2020;22(4):2833–2841.
   Web of Science ®Google Scholar
• Abdollahi-Roodsaz S, Joosten LA, Koenders MI, et al. Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis. J Clin Invest. 2008;118(1):205–216. doi:10.1172/JCI32639
   PubMed Web of Science ®Google Scholar
• Joosten LA, Koenders MI, Smeets RL, et al. Toll-like receptor 2 pathway drives streptococcal cell wall-induced joint inflammation: critical role of myeloid differentiation factor 88. J Immunol. 2003;171(11):6145–6153. doi:10.4049/jimmunol.171.11.6145
   PubMed Web of Science ®Google Scholar
• Ospelt C, Brentano F, Rengel Y, et al. Overexpression of toll-like receptors 3 and 4 in synovial tissue from patients with early rheumatoid arthritis: toll-like receptor expression in early and longstanding arthritis. Arthritis Rheum. 2008;58(12):3684–3692. doi:10.1002/art.24140
   PubMed Web of Science ®Google Scholar
• Roelofs MF, Joosten LA, Abdollahi-Roodsaz S, et al. The expression of toll-like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of toll-like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells. Arthritis Rheum. 2005;52(8):2313–2322. doi:10.1002/art.21278
   PubMed Web of Science ®Google Scholar
• Zimmermann-Geller B, Köppert S, Fischer S, et al. Influence of extracellular RNAs, released by rheumatoid arthritis synovial fibroblasts, on their adhesive and invasive properties. J Immunol. 2016;197(7):2589–2597. doi:10.4049/jimmunol.1501580
   Web of Science ®Google Scholar
• Brentano F, Schorr O, Gay RE, Gay S, Kyburz D. RNA released from necrotic synovial fluid cells activates rheumatoid arthritis synovial fibroblasts via toll-like receptor 3. Arthritis Rheum. 2005;52(9):2656–2665. doi:10.1002/art.21273
   Web of Science ®Google Scholar
• Bokarewa M, Tarkowski A, Lind M, Dahlberg L, Magnusson M. Arthritogenic dsRNA is present in synovial fluid from rheumatoid arthritis patients with an erosive disease course. Eur J Immunol. 2008;38(11):3237–3244. doi:10.1002/eji.200838362
   Web of Science ®Google Scholar
• Hu F, Li Y, Zheng L, et al. Toll-like receptors expressed by synovial fibroblasts perpetuate th1 and th17 cell responses in rheumatoid arthritis. PLoS One. 2014;9(6):e100266. doi:10.1371/journal.pone.0100266
   Web of Science ®Google Scholar
• Bombardieri M, Kam NW, Brentano F, et al. A BAFF/APRIL-dependent TLR3-stimulated pathway enhances the capacity of rheumatoid synovial fibroblasts to induce AID expression and Ig class-switching in B cells. Ann Rheum Dis. 2011;70(10):1857–1865. doi:10.1136/ard.2011.150219
   Web of Science ®Google Scholar
• Kim KW, Cho ML, Oh HJ, et al. TLR-3 enhances osteoclastogenesis through upregulation of RANKL expression from fibroblast-like synoviocytes in patients with rheumatoid arthritis. Immunol Lett. 2009;124(1):9–17. doi:10.1016/j.imlet.2009.02.006
   Web of Science ®Google Scholar
• Zhu W, Meng L, Jiang C, et al. Overexpression of toll-like receptor 3 in spleen is associated with experimental arthritis in rats. Scand J Immunol. 2012;76(3):263–270. doi:10.1111/j.1365-3083.2012.02724.x
   Web of Science ®Google Scholar
• Jiang C, Zhu W, Xu J, et al. MicroRNA-26a negatively regulates toll-like receptor 3 expression of rat macrophages and ameliorates pristane induced arthritis in rats. Arthritis Res Ther. 2014;16(1):R9. doi:10.1186/ar4435
   PubMed Web of Science ®Google Scholar
• Zhu W, Meng L, Jiang C, et al. Arthritis is associated with T-cell-induced upregulation of toll-like receptor 3 on synovial fibroblasts. Arthritis Res Ther. 2011;13(3):R103. doi:10.1186/ar3384
   Web of Science ®Google Scholar
• Lee SY, Yoon BY, Kim JI, et al. Interleukin-17 increases the expression of toll-like receptor 3 via the STAT3 pathway in rheumatoid arthritis fibroblast-like synoviocytes. Immunology. 2014;141(3):353–361. doi:10.1111/imm.12196
   Web of Science ®Google Scholar
• Radstake TRDJ, Roelofs MF, Jenniskens YM, et al. Expression of toll-like receptors 2 and 4 in rheumatoid synovial tissue and regulation by proinflammatory cytokines interleukin-12 and interleukin-18 via interferon-γ. Arthritis Rheum. 2004;50(12):3856–3865. doi:10.1002/art.20678
   PubMed Web of Science ®Google Scholar
• De Rycke L, Vandooren B, Kruithof E, De Keyser F, Veys EM, Baeten D. Tumor necrosis factor α blockade treatment down-modulates the increased systemic and local expression of toll-like receptor 2 and toll-like receptor 4 in spondylarthropathy. Arthritis Rheum. 2005;52(7):2146–2158. doi:10.1002/art.21155
   PubMed Web of Science ®Google Scholar
• Huang Q, Ma Y, Adebayo A, Pope RM. Increased macrophage activation mediated through toll-like receptors in rheumatoid arthritis. Arthritis Rheum. 2007;56(7):2192–2201. doi:10.1002/art.22707
   PubMed Web of Science ®Google Scholar
• Tripathy A, Khanna S, Padhan P, Smita S, Raghav S, Gupta B. Direct recognition of LPS drive TLR4 expressing CD8(+) T cell activation in patients with rheumatoid arthritis. Sci Rep. 2017;7(1):933. doi:10.1038/s41598-017-01033-7
   Web of Science ®Google Scholar
• Zhang Y, Ji T, Ma S, Wu W. MLL1 promotes migration and invasion of fibroblast-like synoviocytes in rheumatoid arthritis by activating the TRIF/NF-κB signaling pathway via H3K4me3 enrichment in the TLR4 promoter region. Int Immunopharmacol. 2020;82:106220. doi:10.1016/j.intimp.2020.106220
   Web of Science ®Google Scholar
• Li D, Zhou Q, Hu G, Wang G. MiRNA-506 inhibits rheumatoid arthritis fibroblast-like synoviocytes proliferation and induces apoptosis by targeting TLR4. Biosci Rep. 2019;39(5):BSR20182500. doi:10.1042/BSR20182500
   Web of Science ®Google Scholar
• Sokolove J, Zhao X, Chandra PE, Robinson WH. Immune complexes containing citrullinated fibrinogen costimulate macrophages via toll-like receptor 4 and Fcγ receptor. Arthritis Rheum. 2011;63(1):53–62. doi:10.1002/art.30081
   PubMed Web of Science ®Google Scholar
• Kiyeko GW, Hatterer E, Herren S, et al. Spatiotemporal expression of endogenous TLR4 ligands leads to inflammation and bone erosion in mouse collagen-induced arthritis. Eur J Immunol. 2016;46(11):2629–2638. doi:10.1002/eji.201646453
   Web of Science ®Google Scholar
• Pierer M, Wagner U, Rossol M, Ibrahim S. Toll-like receptor 4 is involved in inflammatory and joint destructive pathways in collagen-induced arthritis in DBA1J mice. PLoS One. 2011;6(8):e23539–e23539. doi:10.1371/journal.pone.0023539
   PubMed Web of Science ®Google Scholar
• Kim HS, Chung DH. TLR4-mediated IL-12 production enhances IFN-γ and IL-1β production, which inhibits TGF-β production and promotes antibody-induced joint inflammation. Arthritis Res Ther. 2012;14(5):R210–R210. doi:10.1186/ar4048
   PubMed Web of Science ®Google Scholar
• Abdollahi-Roodsaz S, Joosten LAB, Roelofs MF, et al. Inhibition of toll-like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis. Arthritis Rheum. 2007;56(9):2957–2967. doi:10.1002/art.22848
   PubMed Web of Science ®Google Scholar
• Samarpita S, Kim JY, Rasool MK, Kim KS. Investigation of toll-like receptor (TLR) 4 inhibitor TAK-242 as a new potential anti-rheumatoid arthritis drug. Arthritis Res Ther. 2020;22(1):16. doi:10.1186/s13075-020-2097-2
   PubMed Web of Science ®Google Scholar
• Monnet E, Choy EH, McInnes I, et al. Efficacy and safety of NI-0101, an anti-toll-like receptor 4 monoclonal antibody, in patients with rheumatoid arthritis after inadequate response to methotrexate: a phase II study. Ann Rheum Dis. 2020;79(3):316–323. doi:10.1136/annrheumdis-2019-216487
   PubMed Web of Science ®Google Scholar
• Das N, Dewan V, Grace PM, et al. HMGB1 activates proinflammatory signaling via TLR5 leading to allodynia. Cell Rep. 2016;17(4):1128–1140. doi:10.1016/j.celrep.2016.09.076
   Web of Science ®Google Scholar
• Chamberlain ND, Vila OM, Volin MV, et al. TLR5, a novel and unidentified inflammatory mediator in rheumatoid arthritis that correlates with disease activity score and joint TNF-alpha levels. J Immunol. 2012;189(1):475–483. doi:10.4049/jimmunol.1102977
   PubMed Web of Science ®Google Scholar
• Kim SJ, Chen Z, Chamberlain ND, et al. Ligation of TLR5 promotes myeloid cell infiltration and differentiation into mature osteoclasts in rheumatoid arthritis and experimental arthritis. J Immunol. 2014;193(8):3902–3913. doi:10.4049/jimmunol.1302998
   Web of Science ®Google Scholar
• Fu D, Xiao C, Xie Y, Gao J, Ye S. MiR-3926 inhibits synovial fibroblasts proliferation and inflammatory cytokines secretion through targeting toll like receptor 5. Gene. 2019;687:200–206. doi:10.1016/j.gene.2018.11.014
   PubMed Web of Science ®Google Scholar
• Kim SJ, Chen Z, Chamberlain ND, et al. Angiogenesis in rheumatoid arthritis is fostered directly by toll-like receptor 5 ligation and indirectly through interleukin-17 induction. Arthritis Rheum. 2013;65(8):2024–2036. doi:10.1002/art.37992
   Web of Science ®Google Scholar
• Chamberlain ND, Kim SJ, Vila OM, et al. Ligation of TLR7 by rheumatoid arthritis synovial fluid single strand RNA induces transcription of TNFα in monocytes. Ann Rheum Dis. 2013;72(3):418–426. doi:10.1136/annrheumdis-2011-201203
   PubMed Web of Science ®Google Scholar
• Torices S, Alvarez-Rodríguez L, Varela I, et al. Evaluation of toll-like-receptor gene family variants as prognostic biomarkers in rheumatoid arthritis. Immunol Lett. 2017;187:35–40. doi:10.1016/j.imlet.2017.04.011
   Web of Science ®Google Scholar
• Mullen L, Ferdjani J, Sacre S. Simvastatin inhibits toll-like receptor 8 (TLR8) signaling in primary human monocytes and spontaneous tumor necrosis factor production from rheumatoid synovial membrane cultures. Mol Med. 2015;21(1):726–734. doi:10.2119/molmed.2015.00154
   Web of Science ®Google Scholar
• Sacre SM, Lo A, Gregory B, et al. Inhibitors of TLR8 reduce TNF production from human rheumatoid synovial membrane cultures. J Immunol. 2008;181(11):8002–8009. doi:10.4049/jimmunol.181.11.8002
   Web of Science ®Google Scholar
• Sacre S, Medghalchi M, Gregory B, Brennan F, Williams R. Fluoxetine and citalopram exhibit potent antiinflammatory activity in human and murine models of rheumatoid arthritis and inhibit toll-like receptors. Arthritis Rheum. 2010;62(3):683–693. doi:10.1002/art.27304
   Web of Science ®Google Scholar
• Neregård P, Engström M, Agerberth B, Catrina AI. LL-37 is expressed in the inflamed synovium in patients with rheumatoid arthritis and downregulated by TNF inhibitors. Ann Rheum Dis. 2012;71(Suppl 1):A12–A12. doi:10.1136/annrheumdis-2011-201230.26
   Web of Science ®Google Scholar
• Hegewald AB, Breitwieser K, Ottinger SM, et al. Extracellular miR-574-5p induces osteoclast differentiation via TLR 7/8 in rheumatoid arthritis. Front Immunol. 2020;11:585282. doi:10.3389/fimmu.2020.585282
   PubMed Web of Science ®Google Scholar
• Kim S-J, Chen Z, Essani AB, et al. Identification of a novel toll-like receptor 7 endogenous ligand in rheumatoid arthritis synovial fluid that can provoke arthritic joint inflammation. Arthritis Rheumatol. 2016;68(5):1099–1110.
   Web of Science ®Google Scholar
• Alzabin S, Kong P, Medghalchi M, Palfreeman A, Williams R, Sacre S. Investigation of the role of endosomal toll-like receptors in murine collagen-induced arthritis reveals a potential role for TLR7 in disease maintenance. Arthritis Res Ther. 2012;14(3):R142–R142. doi:10.1186/ar3875
   Web of Science ®Google Scholar
• Sacre S, Lo A, Gregory B, et al. Oligodeoxynucleotide inhibition of toll-like receptors 3, 7, 8, and 9 suppresses cytokine production in a human rheumatoid arthritis model. Eur J Immunol. 2016;46(3):772–781. doi:10.1002/eji.201546123
   Web of Science ®Google Scholar
• Chen SY, Shiau AL, Li YT, et al. Suppression of collagen-induced arthritis by intra-articular lentiviral vector-mediated delivery of TOLL-like receptor 7 short hairpin RNA gene. Gene Ther. 2012;19(7):752–760. doi:10.1038/gt.2011.173
   Web of Science ®Google Scholar
• Heil F, Hemmi H, Hochrein H, et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science. 2004;303(5663):1526–1529. doi:10.1126/science.1093620
   PubMed Web of Science ®Google Scholar
• Guiducci C, Gong M, Cepika AM, et al. RNA recognition by human TLR8 can lead to autoimmune inflammation. J Exp Med. 2013;210(13):2903–2919. doi:10.1084/jem.20131044
   PubMed Web of Science ®Google Scholar
• Zhong X-Y, von Mühlenen I, Li Y, et al. Increased concentrations of antibody-bound circulatory cell-free DNA in rheumatoid arthritis. Clin Chem. 2007;53(9):1609–1614. doi:10.1373/clinchem.2006.084509
   Web of Science ®Google Scholar
• Szodoray P, Alex P, Frank MB, et al. A genome-scale assessment of peripheral blood B-cell molecular homeostasis in patients with rheumatoid arthritis. Rheumatology. 2006;45(12):1466–1476. doi:10.1093/rheumatology/kel095
   Web of Science ®Google Scholar
• Miles K, Heaney J, Sibinska Z, et al. A tolerogenic role for toll-like receptor 9 is revealed by B-cell interaction with DNA complexes expressed on apoptotic cells. Proc Natl Acad Sci. 2012;109(3):887–892. doi:10.1073/pnas.1109173109
   Web of Science ®Google Scholar
• Deng G-M, Nilsson I-M, Verdrengh M, Collins LV, Tarkowski A. Intra-articularly localized bacterial DNA containing CpG motifs induces arthritis. Nat Med. 1999;5(6):702–705. doi:10.1038/9554
   PubMed Web of Science ®Google Scholar
• Viglianti GA, Lau CM, Hanley TM, Miko BA, Shlomchik MJ, Marshak-Rothstein A. Activation of autoreactive B cells by CpG dsDNA. Immunity. 2003;19(6):837–847. doi:10.1016/S1074-7613(03)00323-6
   PubMed Web of Science ®Google Scholar
• Fischer A, Abdollahi-Roodsaz S, Böhm C, et al. The involvement of Toll-like receptor 9 in the pathogenesis of erosive autoimmune arthritis. J Cell Mol Med. 2018;22(9):4399–4409. doi:10.1111/jcmm.13735
   Web of Science ®Google Scholar
• Su SB, Tao L, Deng ZP, Chen W, Qin SY, Jiang HX. TLR10: insights, controversies and potential utility as a therapeutic target. Scand J Immunol. 2021;93:e12988.
   Web of Science ®Google Scholar
• Petrackova A, Horak P, Radvansky M, et al. Revealed heterogeneity in rheumatoid arthritis based on multivariate innate signature analysis. Clin Exp Rheumatol. 2020;38(2):289–298.
   Web of Science ®Google Scholar
• Torices S, Julia A, Muñoz P, et al. A functional variant of TLR10 modifies the activity of NFkB and may help predict a worse prognosis in patients with rheumatoid arthritis. Arthritis Res Ther. 2016;18(1):221. doi:10.1186/s13075-016-1113-z
   Web of Science ®Google Scholar
• Elemam NM, Hachim MY, Hannawi S, Maghazachi AA. Differentially expressed genes of natural killer cells can distinguish rheumatoid arthritis patients from healthy controls. Genes (Basel). 2020;11(5):492. doi:10.3390/genes11050492
   PubMed Web of Science ®Google Scholar
• Zhang Y, Cao R, Ying H, et al. Increased expression of TLR10 in B cell subsets correlates with disease activity in rheumatoid arthritis. Mediators Inflamm. 2018;2018:9372436. doi:10.1155/2018/9372436
   Web of Science ®Google Scholar
• Zhang Y, Zheng Y, Li H. NLRP3 inflammasome plays an important role in the pathogenesis of collagen-induced arthritis. Mediators Inflamm. 2016;2016:9656270. doi:10.1155/2016/9656270
   PubMed Web of Science ®Google Scholar
• Guo C, Fu R, Wang S, et al. NLRP3 inflammasome activation contributes to the pathogenesis of rheumatoid arthritis. Clin Exp Immunol. 2018;194(2):231–243. doi:10.1111/cei.13167
   PubMed Web of Science ®Google Scholar
• Choulaki C, Papadaki G, Repa A, et al. Enhanced activity of NLRP3 inflammasome in peripheral blood cells of patients with active rheumatoid arthritis. Arthritis Res Ther. 2015;17(1):257. doi:10.1186/s13075-015-0775-2
   PubMed Web of Science ®Google Scholar
• Zhao C, Gu Y, Zeng X, Wang J. NLRP3 inflammasome regulates Th17 differentiation in rheumatoid arthritis. Clin Immunol. 2018;197:154–160. doi:10.1016/j.clim.2018.09.007
   PubMed Web of Science ®Google Scholar
• Wang Y, Sedlacek AL, Pawaria S, Xu H, Scott MJ, Binder RJ. Cutting edge: the heat shock protein gp96 activates inflammasome-signaling platforms in APCs. J Immunol. 2018;201(8):2209–2214. doi:10.4049/jimmunol.1800505
   PubMed Web of Science ®Google Scholar
• Dong X, Zheng Z, Lin P, et al. ACPAs promote IL-1β production in rheumatoid arthritis by activating the NLRP3 inflammasome. Cell Mol Immunol. 2020;17:261–271.
   PubMed Web of Science ®Google Scholar
• Jäger E, Murthy S, Schmidt C, et al. Calcium-sensing receptor-mediated NLRP3 inflammasome response to calciprotein particles drives inflammation in rheumatoid arthritis. Nat Commun. 2020;11(1):4243. doi:10.1038/s41467-020-17749-6
   Web of Science ®Google Scholar
• Vande Walle L, Van Opdenbosch N, Jacques P, et al. Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis. Nature. 2014;512(7512):69–73. doi:10.1038/nature13322
   PubMed Web of Science ®Google Scholar
• Spalinger MR, Kasper S, Gottier C, et al. NLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase PTPN22. J Clin Invest. 2016;126(5):1783–1800. doi:10.1172/JCI83669
   PubMed Web of Science ®Google Scholar
• Lee YH, Bae SC. Vitamin D level in rheumatoid arthritis and its correlation with the disease activity: a meta-analysis. Clin Exp Rheumatol. 2016;34(5):827–833.
   PubMed Web of Science ®Google Scholar
• Rao Z, Chen X, Wu J, et al. Vitamin D receptor inhibits NLRP3 activation by impeding its BRCC3-mediated deubiquitination. Front Immunol. 2019;10:2783. doi:10.3389/fimmu.2019.02783
   PubMed Web of Science ®Google Scholar
• Thwaites RS, Unterberger S, Chamberlain G, et al. Expression of sterile-α and armadillo motif containing protein (SARM) in rheumatoid arthritis monocytes correlates with TLR2-induced IL-1β and disease activity. Rheumatology. 2021. Available form: https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keab162/6144929. Accessed July 23, 2021.
   Web of Science ®Google Scholar
• Liu Y, Wei W, Wang Y, et al. TNF-α/calreticulin dual signaling induced NLRP3 inflammasome activation associated with HuR nucleocytoplasmic shuttling in rheumatoid arthritis. Inflamm Res. 2019;68(7):597–611. doi:10.1007/s00011-019-01244-w
   Web of Science ®Google Scholar
• Ni M, Wei W, Wang Y, et al. Serum levels of calreticulin in correlation with disease activity in patients with rheumatoid arthritis. J Clin Immunol. 2013;33(5):947–953. doi:10.1007/s10875-013-9885-2
   Web of Science ®Google Scholar
• Tarr JM, Winyard PG, Ryan B, et al. Extracellular calreticulin is present in the joints of patients with rheumatoid arthritis and inhibits FasL (CD95L)-mediated apoptosis of T cells. Arthritis Rheum. 2010;62(10):2919–2929. doi:10.1002/art.27602
   PubMed Web of Science ®Google Scholar
• Wu XY, Li KT, Yang HX, et al. Complement C1q synergizes with PTX3 in promoting NLRP3 inflammasome over-activation and pyroptosis in rheumatoid arthritis. J Autoimmun. 2020;106:102336. doi:10.1016/j.jaut.2019.102336
   PubMed Web of Science ®Google Scholar
• Wang H, Wang Z, Wang L, et al. IL-6 promotes collagen-induced arthritis by activating the NLRP3 inflammasome through the cathepsin B/S100A9-mediated pathway. Int Immunopharmacol. 2020;88:106985. doi:10.1016/j.intimp.2020.106985
   PubMed Web of Science ®Google Scholar
• Anwar MA, Shah M, Kim J, Choi S. Recent clinical trends in Toll-like receptor targeting therapeutics. Med Res Rev. 2019;39(3):1053–1090. doi:10.1002/med.21553
   PubMed Web of Science ®Google Scholar
• Danto S, Shojaee N, Singh R, et al. Efficacy and safety of the selective interleukin-1 receptor associated kinase 4 inhibitor, PF-06650833, in patients with active rheumatoid arthritis and inadequate response to methotrexate [abstract 2909]. Arthritis Rheumatol. 2019;71(S10).
   Google Scholar
• Cohen S, Tuckwell K, Kunder R, et al. Efficacy and safety of fenebrutinib, a BTK inhibitor, compared to placebo in rheumatoid arthritis patients with active disease despite TNF inhibitor treatment: randomized, double blind, Phase 2 Study [abstract 929]. Arthritis Rheumatol. 2019;71(Suppl 10).
   Google Scholar
• Mangan MSJ, Olhava EJ, Roush WR, Seidel HM, Glick GD, Latz E. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discov. 2018;17(8):588. doi:10.1038/nrd.2018.97
   PubMed Web of Science ®Google Scholar
• El-Sharkawy LY, Brough D, Freeman S. Inhibiting the NLRP3 Inflammasome. Molecules. 2020;25(23):5533. doi:10.3390/molecules25235533
   Web of Science ®Google Scholar
• Connolly M, Rooney PR, McGarry T, et al. Acute serum amyloid A is an endogenous TLR2 ligand that mediates inflammatory and angiogenic mechanisms. Ann Rheum Dis. 2016;75(7):1392–1398. doi:10.1136/annrheumdis-2015-207655
   Web of Science ®Google Scholar
• Shi B, Huang Q, Tak PP, et al. SNAPIN: an endogenous toll-like receptor ligand in rheumatoid arthritis. Ann Rheum Dis. 2012;71(8):1411–1417. doi:10.1136/annrheumdis-2011-200899
   PubMed Web of Science ®Google Scholar
• Midwood K, Sacre S, Piccinini AM, et al. Tenascin-C is an endogenous activator of toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nat Med. 2009;15(7):774–780. doi:10.1038/nm.1987
   PubMed Web of Science ®Google Scholar
• Grevers LC, de Vries TJ, Vogl T, et al. S100A8 enhances osteoclastic bone resorption in vitro through activation of toll-like receptor 4: implications for bone destruction in murine antigen-induced arthritis. Arthritis Rheum. 2011;63(5):1365–1375. doi:10.1002/art.30290
   Web of Science ®Google Scholar
• Barreto G, Soininen A, Ylinen P, et al. Soluble biglycan: a potential mediator of cartilage degradation in osteoarthritis. Arthritis Res Ther. 2015;17:379. doi:10.1186/s13075-015-0902-0
   Web of Science ®Google Scholar
• Roelofs MF, Boelens WC, Joosten LAB, et al. Identification of small heat shock protein B8 (HSP22) as a novel TLR4 ligand and potential involvement in the pathogenesis of rheumatoid arthritis. J Immunol. 2006;176(11):7021–7027. doi:10.4049/jimmunol.176.11.7021
   Web of Science ®Google Scholar
• Guillou C, Fréret M, Fondard E, et al. Soluble alpha-enolase activates monocytes by CD14-dependent TLR4 signalling pathway and exhibits a dual function. Sci Rep. 2016;6(1):23796. doi:10.1038/srep23796
   Web of Science ®Google Scholar
• Veiko NN, Shubaeva NO, Ivanova SM, Speranskii AI, Lyapunova NA, Spitkovskii DM. Blood serum DNA in patients with rheumatoid arthritis is considerably enriched with fragments of ribosomal repeats containing immunostimulatory CpG-motifs. Bull Exp Biol Med. 2006;142(3):313–316. doi:10.1007/s10517-006-0354-2
   PubMed Web of Science ®Google Scholar