Synergistic effect of Bruton's tyrosine kinase and TNF‑α in the regulation of rheumatoid arthritis and underlying mechanisms

Du,Jinwan

doi:10.3892/etm.2021.11064

Synergistic effect of Bruton's tyrosine kinase and TNF‑α in the regulation of rheumatoid arthritis and underlying mechanisms

Authors:
- Jinwan Du
View Affiliations

Affiliations: Department of Rheumatology and Immunology, Chongqing Ninth People's Hospital, Beibei, Chongqing 400700, P.R. China
Published online on: December 14, 2021 https://doi.org/10.3892/etm.2021.11064
Article Number: 141

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The presence of Bruton's tyrosine kinase (BTK) in macrophages has been recommended as a promising therapeutic target for rheumatoid arthritis (RA). In addition, activated macrophages in the inflamed joints of patients with RA can also produce a plethora of cytokines, such as TNF‑α. The aim of the present study was to investigate the potential role of BTK and TNF‑α in the regulation of RA. The results demonstrated that higher levels of BTK and TNF‑α were observed in macrophages in inflamed RA joints compared with those in normal joint tissues. Subsequently, the role of BTK and TNF‑α in the regulation of cellular process in inflammatory macrophages was analyzed. It was demonstrated that aberrant expression of BTK and TNF‑α in inflammatory macrophages can lead to higher cell proliferation rates. Once the expression of BTK or TNF‑α was restricted by using short interfering (si)RNAs (siBTK or siTNF‑α), the activity of inflammatory macrophages was significantly downregulated. Of note, when the expression of BTK and TNF‑α was simultaneously decreased, the proliferation rate of inflammatory macrophages was inhibited to the greatest extent. Subsequently, the underlying mechanisms through which BTK and TNF‑α can regulate RA were investigated. The results demonstrated that BTK mainly regulated the ERK/JNK pathway, while TNF‑α mainly affected the inactive rhomboid protein 2/B‑cell‑activating factor pathway. Finally, animal experiments demonstrated that simultaneous silencing of both BTK and TNF‑α can significantly alleviate the symptoms associated with RA.

View Figures

View References

1	De Cock D and Hyrich K: Malignancy and rheumatoid arthritis: Epidemiology, risk factors and management. Best Pract Res Clin Rheumatol. 32:869–886. 2018.PubMed/NCBI View Article : Google Scholar
2	Wasserman AM: Diagnosis and management of rheumatoid arthritis. Am Fam Physician. 84:1245–1252. 2011.PubMed/NCBI
3	Wasserman A: Rheumatoid arthritis: Common questions about diagnosis and management. Am Fam Physician. 97:455–462. 2018.PubMed/NCBI
4	McInnes IB and Schett G: The pathogenesis of rheumatoid arthritis. N Engl J Med. 365:2205–2219. 2011.PubMed/NCBI View Article : Google Scholar
5	Croia C, Bursi R, Sutera D, Petrelli F, Alunno A and Puxeddu I: One year in review 2019: Pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol. 37:347–357. 2019.PubMed/NCBI
6	Udalova IA, Mantovani A and Feldmann M: Macrophage heterogeneity in the context of rheumatoid arthritis. Nat Rev Rheumatol. 12:472–485. 2016.PubMed/NCBI View Article : Google Scholar
7	Rana AK, Li Y, Dang Q and Yang F: Monocytes in rheumatoid arthritis: Circulating precursors of macrophages and osteoclasts and, their heterogeneity and plasticity role in RA pathogenesis. Int Immunopharmacol. 65:348–359. 2018.PubMed/NCBI View Article : Google Scholar
8	Huang QQ, Birkett R, Doyle R, Shi B, Roberts EL, Mao Q and Pope RM: The role of macrophages in the response to TNF inhibition in experimental arthritis. J Immunol. 200:130–138. 2018.PubMed/NCBI View Article : Google Scholar
9	de La Forest Divonne M, Gottenberg JE and Salliot C: Safety of biologic DMARDs in RA patients in real life: A systematic literature review and meta-analyses of biologic registers. Joint Bone Spine. 84:133–140. 2017.PubMed/NCBI View Article : Google Scholar
10	Massalska M, Maslinski W and Ciechomska M: Small molecule inhibitors in the treatment of rheumatoid arthritis and beyond: Latest updates and potential strategy for fighting COVID-19. Cells. 9(1876)2020.PubMed/NCBI View Article : Google Scholar
11	Ternant D, Bejan-Angoulvant T, Passot C, Mulleman D and Paintaud G: Clinical pharmacokinetics and pharmacodynamics of monoclonal antibodies approved to treat rheumatoid arthritis. Clin Pharmacokinet. 54:1107–1123. 2015.PubMed/NCBI View Article : Google Scholar
12	Accortt NA, Bonafede MM, Collier DH, Iles J and Curtis JR: Risk of subsequent infection among patients receiving tumor necrosis factor inhibitors and other disease-modifying antirheumatic drugs. Arthritis Rheumatol. 68:67–76. 2016.PubMed/NCBI View Article : Google Scholar
13	Lv J, Wu J, He F, Qu Y, Zhang Q and Yu C: Development of Bruton's tyrosine kinase inhibitors for rheumatoid arthritis. Curr Med Chem. 25:5847–5859. 2018.PubMed/NCBI View Article : Google Scholar
14	Hendriks RW, Yuvaraj S and Kil LP: Targeting Bruton's tyrosine kinase in B cell malignancies. Nat Rev Cancer. 14:219–232. 2014.PubMed/NCBI View Article : Google Scholar
15	Norman P: Investigational Bruton's tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Expert Opin Investig Drugs. 25:891–899. 2016.PubMed/NCBI View Article : Google Scholar
16	Hsu J, Gu Y, Tan SL, Narula S, DeMartino JA and Liao C: Bruton's Tyrosine Kinase mediates platelet receptor-induced generation of microparticles: A potential mechanism for amplification of inflammatory responses in rheumatoid arthritis synovial joints. Immunol Lett. 150:97–104. 2013.PubMed/NCBI View Article : Google Scholar
17	Whang JA and Chang BY: Bruton's tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Drug Discov Today. 19:1200–1204. 2014.PubMed/NCBI View Article : Google Scholar
18	Di Paolo JA, Huang T, Balazs M, Barbosa J, Barck KH, Bravo BJ, Carano RA, Darrow J, Davies DR, DeForge LE, et al: Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis. Nat Chem Biol. 7:41–50. 2011.PubMed/NCBI View Article : Google Scholar
19	Wu J, Zhu Z, Yu Q and Ding C: Tyrosine kinase inhibitors for the treatment of rheumatoid arthritis: Phase I to Ⅱ clinical trials. Expert Opin Investig Drugs. 28:1113–1123. 2019.PubMed/NCBI View Article : Google Scholar
20	Erickson RI, Schutt LK, Tarrant JM, McDowell M, Liu L, Johnson AR, Lewin-Koh SC, Hedehus M, Ross J, Carano RA, et al: Bruton's tyrosine kinase small molecule inhibitors induce a distinct pancreatic toxicity in rats. J Pharmacol Exp Ther. 360:226–238. 2017.PubMed/NCBI View Article : Google Scholar
21	Gowhari Shabgah A, Shariati-Sarabi Z, Tavakkol-Afshari J, Ghasemi A, Ghoryani M and Mohammadi M: A significant decrease of BAFF, APRIL, and BAFF receptors following mesenchymal stem cell transplantation in patients with refractory rheumatoid arthritis. Gene. 732(144336)2020.PubMed/NCBI View Article : Google Scholar
22	Li J, Hsu HC and Mountz JD: Managing macrophages in rheumatoid arthritis by reform or removal. Curr Rheumatol Rep. 14:445–454. 2012.PubMed/NCBI View Article : Google Scholar
23	Moura RA, Quaresma C, Vieira AR, Gonçalves MJ, Polido-Pereira J, Romão VC, Martins N, Canhão H and Fonseca JE: B-cell phenotype and IgD-CD27- memory B cells are affected by TNF-inhibitors and tocilizumab treatment in rheumatoid arthritis. PLoS One. 12(e0182927)2017.PubMed/NCBI View Article : Google Scholar
24	Schiff M, Combe B, Dörner T, Kremer JM, Huizinga TW, Veenhuizen M, Gill A, Komocsar W, Berclaz PY, Ortmann R, et al: Efficacy and safety of tabalumab, an anti-BAFF monoclonal antibody, in patients with moderate-to-severe rheumatoid arthritis and inadequate response to TNF inhibitors: Results of a randomised, double-blind, placebo-controlled, phase 3 study. RMD Open. 1(e000037)2015.PubMed/NCBI View Article : Google Scholar
25	Zhao G, Liu A, Zhang Y, Zuo ZQ, Cao ZT, Zhang HB, Xu CF and Wang J: Nanoparticle-delivered siRNA targeting Bruton's tyrosine kinase for rheumatoid arthritis therapy. Biomater Sci. 7:4698–4707. 2019.PubMed/NCBI View Article : Google Scholar
26	Chang BY, Huang MM, Francesco M, Chen J, Sokolove J, Magadala P, Robinson WH and Buggy JJ: The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells. Arthritis Res Ther. 13(R115)2011.PubMed/NCBI View Article : Google Scholar
27	Cao Y, Lu G, Chen X, Chen X, Guo N and Li W: BAFF is involved in the pathogenesis of IgA nephropathy by activating the TRAF6/NF-κB signaling pathway in glomerular mesangial cells. Mol Med Rep. 21:795–805. 2020.PubMed/NCBI View Article : Google Scholar
28	O'Neil LJ and Kaplan MJ: Neutrophils in rheumatoid arthritis: breaking immune tolerance and fueling disease. Trends Mol Med. 25:215–227. 2019.PubMed/NCBI View Article : Google Scholar
29	Calabresi E, Petrelli F, Bonifacio AF, Puxeddu I and Alunno A: One year in review 2018: Pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol. 36:175–184. 2018.PubMed/NCBI
30	Boissier MC, Semerano L, Challal S, Saidenberg-Kermanac'h N and Falgarone G: Rheumatoid arthritis: From autoimmunity to synovitis and joint destruction. J Autoimmun. 39:222–228. 2012.PubMed/NCBI View Article : Google Scholar
31	Kurowska-Stolarska M and Alivernini S: Synovial tissue macrophages: Friend or foe? RMD Open. 3(e000527)2017.PubMed/NCBI View Article : Google Scholar
32	Thalhamer T, McGrath MA and Harnett MM: MAPKs and their relevance to arthritis and inflammation. Rheumatology (Oxford). 47:409–414. 2008.PubMed/NCBI View Article : Google Scholar
33	Schett G, Tohidast-Akrad M, Smolen JS, Schmid BJ, Steiner CW, Bitzan P, Zenz P, Redlich K, Xu Q and Steiner G: Activation, differential localization, and regulation of the stress-activated protein kinases, extracellular signal-regulated kinase, c-JUN N-terminal kinase, and p38 mitogen-activated protein kinase, in synovial tissue and cells in rheumatoid arthritis. Arthritis Rheum. 43:2501–2512. 2000.PubMed/NCBI View Article : Google Scholar
34	Salojin KV, Owusu IB, Millerchip KA, Potter M, Platt KA and Oravecz T: Essential role of MAPK phosphatase-1 in the negative control of innate immune responses. J Immunol. 176:1899–1907. 2006.PubMed/NCBI View Article : Google Scholar
35	Shabgah AG, Shariati-Sarabi Z, Tavakkol-Afshari J and Mohammadi M: The role of BAFF and APRIL in rheumatoid arthritis. J Cell Physiol. 234:17050–17063. 2019.PubMed/NCBI View Article : Google Scholar
36	Wei F, Chang Y and Wei W: The role of BAFF in the progression of rheumatoid arthritis. Cytokine. 76:537–544. 2015.PubMed/NCBI View Article : Google Scholar
37	Lichtenthaler SF: iRHOM2 takes control of rheumatoid arthritis. J Clin Invest. 123:560–562. 2013.PubMed/NCBI View Article : Google Scholar
38	Siggs OM, Xiao N, Wang Y, Shi H, Tomisato W, Li X, Xia Y and Beutler B: iRhom2 is required for the secretion of mouse TNFα. Blood. 119:5769–5771. 2012.PubMed/NCBI View Article : Google Scholar