Inhibitory effect of anti-malarial agents on the expression of proinflammatory chemokines via Toll-like receptor 3 signaling in human glomerular endothelial cells
Riko Sato, Tadaatsu Imaizumi, Tomomi Aizawa, Shojiro Watanabe, Koji Tsugawa, Shogo Kawaguchi, Kazuhiko Seya, Tomoh Matsumiya, Hiroshi Tanaka, Riko Sato, Tadaatsu Imaizumi, Tomomi Aizawa, Shojiro Watanabe, Koji Tsugawa, Shogo Kawaguchi, Kazuhiko Seya, Tomoh Matsumiya, Hiroshi Tanaka
Abstract
Objective: Although anti-malarial agents, chloroquine (CQ) and hydroxychloroquine (HCQ) are currently used for the treatment of systemic lupus erythematosus, their efficacy for lupus nephritis (LN) remains unclear. Given that upregulation of glomerular Toll-like receptor 3 (TLR3) signaling plays a pivotal role in the pathogenesis of LN, we examined whether CQ and HCQ affect the expression of the TLR3 signaling-induced representative proinflammatory chemokines, monocyte chemoattractant protein-1 (MCP-1), and C-C motif chemokine ligand 5 (CCL5) in cultured human glomerular endothelial cells (GECs).
Methods: We examined the effect of polyinosinic-polycytidylic acid (poly IC), an agonist of TLR3, on MCP-1, CCL5 and interferon (IFN)-β expression in GECs. We then analyzed whether pretreatment with CQ, HCQ, or dexamethasone (DEX) inhibits poly IC-induced expression of these chemokines using real-time quantitative reverse transcriptase PCR and ELISA. Phosphorylation of signal transducers and activator of transcription protein 1 (STAT1) was examined using western blotting.
Results: Poly IC increased MCP-1 and CCL5 expression in a time- and concentration-dependent manner in GECs. Pretreating cells with CQ, but not DEX, attenuated poly IC-induced MCP-1 and CCL5 expression; however, HCQ pretreatment attenuated poly IC-induced CCL5, but not MCP-1. HCQ did not affect the expression of IFN-β and phosphorylation of STAT-1.
Conclusion: Considering that TLR3 signaling is implicated, at least in part, in LN pathogenesis, our results suggest that anti-malarial agents exert a protective effect against the development of inflammation in GECs, as postulated in LN. Interestingly, CQ is a rather powerful inhibitor compared with HCQ on TLR3 signaling-induced chemokine expression in GECs. In turn, these findings may further support the theory that the use of HCQ is safer than CQ in a clinical setting. However, further detailed studies are needed to confirm our preliminary findings.
Keywords: Chloroquine; Toll-like receptor 3; glomerular endothelial cells; hydroxychloroquine; lupus nephritis.
Conflict of interest statement
No potential conflict of interest was reported by the author(s).
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References
- Bruggeman LA. Common mechanisms of viral injury to the kidney. Adv Chronic Kidney Dis. 2019;26(3):164–170.
- Robson MG. Toll-like receptors and renal disease. Nephron Exp Nephrol. 2009;113(1):e1–e7.
- Anders HJ. Pseudoviral immunity - a novel concept for lupus. Trends Mol Med. 2009;15(12):553–561.
- Tanaka H, Imaizumi T.. Inflammatory chemokine expression via toll-like receptor 3 signaling in normal human mesangial cells. Clin Dev Immunol. 2013;2013:984708.
- Lorenz G, Lech M, Anders HJ.. Toll-like receptor activation in the pathogenesis of lupus nephritis. Clin Immunol. 2017;185:86–94.
- Hagberg N, Rönnblom L.. Systemic lupus erythematosus-a disease with a dysregulated type I interferon system. Scand J Immunol. 2015;82(3):199–207.
- Conti F, Spinelli FR, Truglia S, et al. . Kidney expression of Toll like receptors in lupus nephritis: quantification and clinicopathological correlations. Mediators Inflamm. 2016;2016:7697592.
- Hägele H, Allam R, Pawar RD, et al. . Double-stranded RNA activates type I interferon secretion in glomerular endothelial cells via retinoic acid-inducible gene (RIG)-1. Nephrol Dial Transplant. 2009;24(11):3312–3318.
- Liu Q, Imaizumi T, Kawaguchi S, et al. . Toll-like receptor 3 signaling contributes to regional neutrophil recruitment in cultured human glomerular endothelial cells. Nephron. 2018;139(4):349–358.
- Aizawa T, Imaizumi T, Hirono K, et al. . Chloroquine attenuates TLR3-mediated plasminogen activator inhibitor-1 expression in cultured human glomerular endothelial cells. Clin Exp Nephrol. 2019;23(4):448–454.
- Liu Q, Imaizumi T, Aizawa T, et al. . Cytosolic sensors of viral RNA are involved in the production of interleukin-6 via Toll-like receptor 3 signaling in human glomerular endothelial cells. Kidney Blood Press Res. 2019;44(1):62–71.
- Hirono K, Imaizumi T, Aizawa T, et al. . Endothelial expression of fractalkine (CX3CL1) is induced by Toll-like receptor 3 signaling in cultured human glomerular endothelial cells. Mod Rheumatol. 2020;30(6):1074–1081.
- Bertsias G, Tektonidou M, Amoura Z, et al. . Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adults and paediatric lupus nephritis. Ann Rheum Dis. 2012;71(11):1771–1782.
- Kuznik A, Bencina M, Svajger U, et al. . Mechanism of endosomal TLR inhibition by antimalarial drugs and imidazoquinolines. J Immunol. 2011;186(8):4794–4804.
- Imaizumi T, Hayakari R, Matsumiya T, et al. . Chloroquine attenuates TLR3/IFN-β signaling in cultured normal human mesangial cells: a possible protective effect against renal damage in lupus nephritis. Mod Rheumatol. 2017;27(6):1004–1009.
- Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, et al. . Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis. 2010;69(1):20–28.
- Kawai T, Akira S.. TLR signaling. Cell Death Differ. 2006;13(5):816–825.
- Watanabe S, Imaizumi T, Tsuruga K, et al. . Glomerular expression of myxovirus resistance protein 1 in human mesangial cells: possible activation of innate immunity in the pathogenesis of lupus nephritis. Nephrology. 2013;18(12):833–837.
- Dörner T. Therapy: hydroxychloroquine in SLE: old drug, new perspectives. Nat Rev Rheumatol. 2010;6(1):10–11.
- Kuznik A, Bencina M, Svajger U, et al. . Mechanism of endosomal TLR inhibition by antimalarial drugs and imidazoquinolines. J Immunol. 2011;186:794–804.
- Cunha C, Alexander S, Ashby D, et al. . Hydroxycloroquine blood concentration in lupus nephritis: a determinant of disease outcome? Nephrol Dial Transplant. 2018;33:1604–1610.
- Schroeder RL, Gerber JP.. Chloroquine and hydroxychloroquine binding to melanin: some possible consequences for pathologies. Toxicol Rep. 2014;1:963–968.
- Sundelin SP, Terman A.. Different effects of chloroquine and hydroxychloroquine on lysosomal function in cultured retinal pigment epithelial cells. APMIS. 2002;110(6):481–489.
Source: PubMed