Abstract
Cell signaling is considered a part of a network for communication that regulates basic cellular activities. The ability of cells to communicate correctly to the surrounding environment has an important role in development, tissue repair, and immunity as well as normal tissue homeostasis. Dysregulated activation and crosstalk between many intracellular signaling pathways are implicated in the pathogenesis of rheumatoid arthritis (RA), such as the Janus Kinase/signal transducers and activators of transcription (JAK/STAT), Toll-like receptor/nuclear factor kappa B (TLR/NF-κB), phosphatidylinositide-3Kinase/protein kinase B/mammalian target of rapamycin (PI-3K/AKT/mTOR), the stress activated protein kinase/mitogen-activated protein kinase (SAPK/MAPK), and spleen tyrosine kinase (SYK) pathways. Other interrelated pathways that can be targeted to halt the inflammatory status in the disease are purinergic 2X7 receptor (P2X7R)/nucleotide binding oligomerization domain-like receptor family pyrin domain containing 3 or inflammasome (NLRP-3)/NF-κB and Notch pathways. In this review, we will show the orchestrated modulation in the pathogenesis of RA via the crossregulation between dysregulated signaling pathways which can mediate a sustained loop of activation for these signaling pathways as well as aggrevate the inflammatory condition. Also, this review will highlight many targets that can be useful in the development of more effective therapeutic options.
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References
Aksoy E, Taboubi S, Torres D, Delbauve S, Hachani A, Whitehead MA et al (2012) The p110delta isoform of the kinase PI-3K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock. Nat Immunol 13:1045–1054. https://doi.org/10.1038/ni.2426
Al-Rasheed NM, Al-Rasheed NM, Hasan IH, Al-Amin MA, Al-Ajmi HN, Mahmoud AM (2016) Sitagliptin attenuates cardiomyopathy by modulating the JAK/STAT signaling pathway in experimental diabetic rats. Drug Des Dev Ther 10:2095–2107. https://doi.org/10.2147/DDDT.S109287
Ambili R, Janam P (2017) A critique on nuclear factor-kappa B and signal transducer and activator of transcription 3: the key transcription factors in periodontal pathogenesis. J Indian Soc Periodontol 21:350–356. https://doi.org/10.4103/jisp.jisp_301_16
Bose S, Banerjee S, Mondal A, Chakraborty U, Pumarol J, Croley C (2020) Targeting the JAK/STAT signaling pathway using phytocompounds for cancer prevention and therapy. Cells 9:1451. https://doi.org/10.3390/cells9061451
Branimir A, Miroslav M (2014) Pathogenesis of rheumatoid arthritis. Reumatizam 61:19–23
Burnstock G, Knight GE (2018) The potential of P2X7 receptors as a therapeutic target, including inflammation and tumor progression. Purinergic Signal 14:1–18. https://doi.org/10.1007/s11302-017-9593-0
Choi BY, Choi Y, Park JS, Kang LJ, Baek SH, Park JS et al (2018) Inhibition of Notch1 induces population and suppressive activity of regulatory T cell in inflammatory arthritis. Theranostics 8:231–243. https://doi.org/10.7150/thno.26093
Choulaki C, Papadaki G, Repa A, Kampouraki E, Kambas K, Ritis K et al (2015) Enhanced activity of NLRP3 inflammasome in peripheral blood cells of patients with active rheumatoid arthritis. Arthritis Res Ther 17:257. https://doi.org/10.1186/s13075-015-0775-2
Choy E (2012) Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology (Oxford) 51:v3–v11. https://doi.org/10.1093/rheumatology/kes113
Deng GM, Kyttaris VC, Tsokos GC (2016) Targeting SYK in autoimmune rheumatic diseases. Front Immunol 7:78. https://doi.org/10.3389/fimmu.2016.00078
Duffy L, O’Reilly SC (2016) Toll-like receptors in the pathogenesis of autoimmune diseases: recent and emerging translational developments. Immunotargets Ther 5:69–80. https://doi.org/10.2147/ITT.S89795
Fan ZD, Zhang YY, Guo YH, Huang N, Ma HH, Huang H et al (2016) Involvement of P2X7 receptor signaling on regulating the differentiation of Th17 cells and type II collagen-induced arthritis in mice. Sci Rep 6:35804. https://doi.org/10.1038/srep35804
Fang Q, Zhou C, Nandakumar KS (2020) Molecular and cellular pathways contributing to joint damage in rheumatoid arthritis. Mediators Inflamm 2020:3830212. https://doi.org/10.1155/2020/3830212
Fioravanti A, Tenti S, McAllister M, Chemaly M, Eakin A, McLaughlin J et al (2019) Exploring the involvement of NLRP3 and IL-1β in osteoarthritis of the hand: results from a pilot study. Mediators Inflamm 2019:1–11. https://doi.org/10.1155/2019/2363460
Fusco R, Siracusa R, Genovese T, Cuzzocrea S, Di Paola R (2020) Focus on the role of NLRP3 inflammasome in diseases. Int J Mol Sci 21:4223. https://doi.org/10.3390/ijms21124223
Guo H, Sun L, Ling S, Xu JW (2018) Levistilide A ameliorates NLRP3 EXPRESSION INVOLVING the SYK-p38/JNK pathway and peripheral obliterans in rats. Mediators Inflamm 12:1–11. https://doi.org/10.1155/2018/7304096
Hartung JE, Eskew O, Wong T, Tchivileva IE, Oladosu FA, O’Buckley SC et al (2015) Nuclear factor-kappa B regulates pain and COMT expression in a rodent model of inflammation. Brain Behav Immun 50:196–202. https://doi.org/10.1016/j.bbi.2015.07.014
Heinrich PC, Behrmann I, Haan S, Hermanns HM, Müller-Newen G, Schaper F (2003) Principles of interleukin (IL)-6-type cytokine signaling and its regulation. Biochem J 374:1–20. https://doi.org/10.1042/BJ20030407
Huang QQ, Pope RM (2009) The role of toll-like receptors in rheumatoid arthritis. Curr Rheumatol Rep 11:357–364. https://doi.org/10.1007/s11926-009-0051-z
Ibrahim S, Salama M, Selima E, Refaat R (2020) Sitagliptin and tofacitinib ameliorate adjuvant induced arthritis via modulating the cross talk between JAK/STAT and TLR-4/NF-κB signaling pathways. Life Sci 2020:118261. https://doi.org/10.1016/j.lfs.2020.118261
Joosten LA, Abdollahi-Roodsaz S, Dinarello CA, O’Neill L, Netea MG (2016) Toll-like receptors and chronic inflammation in rheumatic diseases: new developments. Nat Rev Rheumatol 12:344–357. https://doi.org/10.1038/nrrheum.2016.61
Keewan E, Naser SA (2020) The role of notch signaling in macrophages during inflammation and infection: implication in rheumatoid arthritis? Cells 9:111. https://doi.org/10.3390/cells9010111
Kim MJ, Park JS, Lee SJ, Jang J, Park JS, Back SH et al (2015) Notch1 targeting siRNA delivery nanoparticles for rheumatoid arthritis therapy. J Control Release 216:140–148. https://doi.org/10.1016/j.jconrel.2015.08.025
Li Z, Guo J, Bi L (2020) Role of the NLRP3 inflammasome in autoimmune diseases. Biomed Pharmacother 130:110542. https://doi.org/10.1016/j.biopha.2020.110542
Liu T, Zhang L, Joo D, Sun SC (2017) NF-kappaB signaling in inflammation. Signal Transduct Target Ther 2:17023. https://doi.org/10.1038/sigtrans.2017.23
Liu K, Zhang Y, Liu L, Yuan Q (2019) miR-125 regulates PI-3K /Akt/mTOR signaling pathway in rheumatoid arthritis rats via PARP2. Biosci Rep. 39:BSR20180890. https://doi.org/10.1042/BSR20180890
Liu Y, Wu Y, Gu S, Yin Q, Li H, Wang J et al (2020) The P2X7 receptor (P2X7R)-specific antagonist A804598 inhibits inflammatory reaction in human fibroblast-like synoviocytes. Am J Transl Res 12:45–53
López-López S, Monsalve EM, Romero de Ávila MJ et al (2020) NOTCH3 signaling is essential for NF-κB activation in TLR-activated macrophages. Sci Rep 10:14839. https://doi.org/10.1038/s41598-020-71810-4
Lowell CA (2011) Src-family and SYK kinases in activating and inhibitory pathways in innate immune cells: signaling cross talk. Cold Spring Harb Perspect Biol 3:a002352. https://doi.org/10.1101/cshperspect.a002352
Lundquist LM, Cole SW, Sikes ML (2014) Efficacy and safety of tofacitinib for treatment of rheumatoid arthritis. World J Orthop 5:504–511. https://doi.org/10.5312/wjo.v5.i4.504
Malemud CJ (2013) Intracellular signaling pathways in rheumatoid arthritis. J Clin Cell Immunol 4:160. https://doi.org/10.4172/2155-9899.1000160
Martínez-Limón A, Joaquin M, Caballero M, Posas F, de Nadal E (2020) The p38 pathway: from biology to cancer therapy. Int J Mol Sci 21:1913. https://doi.org/10.3390/ijms21061913
McInnes IB, Liew FY (2005) Cytokine networks–towards new therapies for rheumatoid arthritis. Nat Clin Pract Rheumatol 1:31–39. https://doi.org/10.1038/ncprheum0020
Mori T, Miyamoto T, Yoshida H, Asakawa M, Kawasumi M, Kobayashi T et al (2011) IL-1beta and TNFalpha-initiated IL-6-STAT3 pathway is critical in mediating inflammatory cytokines and RANKL expression in inflammatory arthritis. Int Immunol 23:701–712. https://doi.org/10.1093/intimm/dxr077
Okamoto H, Kobayashi A (2011) Tyrosine kinases in rheumatoid arthritis. J Inflamm (Lond Engl) 8:21. https://doi.org/10.1186/1476-9255-8-21
Ospelt C, Brentano F, Rengel Y, Stanczyk J, Kolling C, Tak PP et al (2008) 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 58:3684–3692. https://doi.org/10.1002/art.24140
O’Sullivan LA, Liongue C, Lewis RS, Stephenson SE, Ward AC (2007) Cytokine receptor signaling through the Jak-Stat-Socs pathway in disease. Mol Immunol 44:2497–2506. https://doi.org/10.1016/j.molimm.2006.11.025
Park JS, Kim SH, Kim K, Jin CH, Choi KY, Jang J et al (2015) Inhibition of notch signalling ameliorates experimental inflammatory arthritis. Ann Rheum Dis 74:267–274. https://doi.org/10.1136/annrheumdis-2013-203467
Pesu M, Laurence A, Kishore N, Zwillich SH, Chan G, O’Shea JJ (2008) Therapeutic targeting of Janus kinases. Immunol Rev 223:132–142. https://doi.org/10.1111/j.1600-065X.2008.00644.x
Rawlings JS, Rosler KM, Harrison DA (2004) The JAK/STAT signaling pathway. J Cell Sci 117:1281–1283. https://doi.org/10.1242/jcs.00963
Ruscitti P, Cipriani P, Di Benedetto P, Liakouli V, Berardicurti O, Carubbi F et al (2015) Monocytes from patients with rheumatoid arthritis and type 2 diabetes mellitus display an increased production of interleukin (IL)-1β via the nucleotide-binding domain and leucine-rich repeat containing family pyrin 3 (NLRP3)-inflammasome activation: a possible implication for therapeutic decision in these patients. Clin Exp Immunol 182:35–44. https://doi.org/10.1111/cei.12667
Shang Y, Smith S, Hu X (2016) Role of Notch signaling in regulating innate immunity and inflammation in health and disease. Protein Cell 7:159–174. https://doi.org/10.1007/s13238-016-0250-0
Shuai K, Liu B (2003) Regulation of JAK-STAT signalling in the immune system. Nat Rev Immunol 3:900–911. https://doi.org/10.1038/nri1226
Singh S, Singh S (2020) JAK-STAT inhibitors: Immersing therapeutic approach for management of rheumatoid arthritis. Int Immunopharmacol 86:106731. https://doi.org/10.1016/j.intimp.2020.10673
Sun W, Zhang H, Wang H, Chiu YG, Wang M, Ritchlin CT et al (2017) Targeting notch-activated M1 macrophages attenuates joint tissue damage in a mouse model of inflammatory arthritis. J Bone Miner Res 32:1469–1480. https://doi.org/10.1002/jbmr.3117
Xie S, Chen M, Yan B, He X, Chen X, Li D (2014) Identification of a role for the PI-3K/AKT/mTOR signaling pathway in innate immune cells. PLoS ONE 9:e94496. https://doi.org/10.1371/journal.pone.0094496
Zeng D, Yao P, Zhao H (2019) P2X7, a critical regulator and potential target for bone and joint diseases. J Cell Physiol 234:2095–2103
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Ibrahim, S.S.A., Huttunen, K.M. Orchestrated modulation of rheumatoid arthritis via crosstalking intracellular signaling pathways. Inflammopharmacol 29, 965–974 (2021). https://doi.org/10.1007/s10787-021-00800-3
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DOI: https://doi.org/10.1007/s10787-021-00800-3