Inhibiting Notch‑1 reduces the expression of Toll‑like receptor 9 in BABL/C‑lpr mouse kidneys and improves glucocorticoid sensitivity

Xiao,Gong; Ning,Wangbin; Zhang,Chunhu; Wu,Shiyao; Zuo,Xiaoxia

doi:10.3892/mmr.2015.3758

Inhibiting Notch‑1 reduces the expression of Toll‑like receptor 9 in BABL/C‑lpr mouse kidneys and improves glucocorticoid sensitivity

Authors:
- Gong Xiao
- Wangbin Ning
- Chunhu Zhang
- Shiyao Wu
- Xiaoxia Zuo
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Affiliations: Department of Rheumatology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China, Department of Chinese Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
Published online on: May 8, 2015 https://doi.org/10.3892/mmr.2015.3758
Pages: 2765-2770

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Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, characterized by the development of a pathogenic autoantibodies. Lupus nephritis is a major cause of mortality in patients with SLE. Glucocorticoids are used for the treatment of lupus, however, corticosteroids have no effect on the expression of Toll‑like receptor 9 (TLR9), which may limit response to corticosteroids in certain patients with SLR. The expression of TLR9 can be used as a predictor of glucocorticoid response in patients with active SLE. The present study analyzed urine proteins and pathological kidney sections of BABL/C‑lpr mice and found that, following the inhibition of Notch1, glucocorticoid treatment improved the symptoms of lupus nephritis. Furthermore, glucocorticoid treatment reduced the expression of TLR9 in the BABL/C‑lpr mouse kidneys, according to immunohistochemical and western blot analyses. These results suggested that inhibition of the expression of Notch‑1 enhanced corticosteroid sensitivity in BABL/C‑lpr mice.

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1	D’Cruz DP, Khamashta MA and Hughes GR: Systemic lupus erythematosus. Lancet. 369:587–596. 2007. View Article : Google Scholar
2	Borchers AT, Leibushor N, Naguwa SM, et al: Lupus nephritis: A critical review. Autoimmun Rev. 12:174–194. 2012. View Article : Google Scholar : PubMed/NCBI
3	Mak A and Kow NY: The pathology of T cells in systemic lupus erythematosus. J Immunol Res. 2014:4190292014. View Article : Google Scholar : PubMed/NCBI
4	Mackern-Oberti JP, Llanos C, Vega F, et al: Role of dendritic cells in the initiation, progress and modulation of systemic autoimmune diseases. Autoimmun Rev. 14:127–139. 2015. View Article : Google Scholar
5	Al Gadban MM, Alwan MM, Smith KJ and Hammad SM: Accelerated vascular disease in systemic lupus erythematosus: Role of macrophage. Clin Immunol. 157:133–144. 2015. View Article : Google Scholar : PubMed/NCBI
6	Laky K, Evans S, Perez-Diez A and Fowlkes BJ: Notch signaling regulates antigen sensitiviy of naive CD4+ T cells by tuning co-stimulation. Immunity. 42:80–94. 2015. View Article : Google Scholar : PubMed/NCBI
7	Ohishi K, Varnum-Finney B, Serda RE, et al: The Notch ligand, Delta-1, inhibits the differentiation of monocytes into macrophages but permits their differentiation into dendritic cells. Blood. 98:1402–1407. 2001. View Article : Google Scholar : PubMed/NCBI
8	Cheng P, Zhou J and Gabrilovich D: Regulation of dendritic cell differentiation and function by Notch and Wnt pathways. Immunol Rev. 234:105–119. 2010. View Article : Google Scholar : PubMed/NCBI
9	Backer RA, Helbig C, Gentek R, et al: A central role for Notch in effector CD8(+) T cell differentiation. Nat Immunol. 15:1143–1151. 2014. View Article : Google Scholar : PubMed/NCBI
10	Zheng J, Jiang HY, Li J, et al: Microrna-23b promotes tolerogenic properties of dendritic cells in vitro through inhibiting notch1/nf-kappab signalling pathways. Allergy. 67:362–370. 2012. View Article : Google Scholar : PubMed/NCBI
11	Dervovic DD, Liang HC, Cannons JL, et al: Cellular and molecular requirements for the selection of in vitro-generated cd8 t cells reveal a role for notch. J Immunol. 191:1704–1715. 2013. View Article : Google Scholar : PubMed/NCBI
12	Riella LV, Ueno T, Batal I, et al: Blockade of notch ligand delta1 promotes allograft survival by inhibiting alloreactive th1 cells and cytotoxic t cell generation. J Immunol. 187:4629–4638. 2011. View Article : Google Scholar : PubMed/NCBI
13	Amsen D, Blander JM, Lee GR, et al: Instruction of distinct cd4 t helper cell fates by different notch ligands on antigen-presenting cells. Cell. 117:515–526. 2004. View Article : Google Scholar : PubMed/NCBI
14	Dongre A, Surampudi L, Lawlor RG, et al: Non-canonical Notch signaling drives activation and differentiation of peripheral CD4(+) T cells. Front Immunol. 5:542014. View Article : Google Scholar : PubMed/NCBI
15	Artavanis-Tsakonas S, Rand MD and Lake RJ: Notch signaling: Cell fate control and signal integration in development. Science. 284:770–776. 1999. View Article : Google Scholar : PubMed/NCBI
16	Talora C, Campese AF, Bellavia D, et al: Notch signaling and diseases: An evolutionary journey from a simple beginning to complex outcomes. Biochim Biophys Acta. 1782:489–497. 2008. View Article : Google Scholar : PubMed/NCBI
17	Zhang W, Xu W and Xiong S: Blockade of notch1 signaling alleviates murine lupus via blunting macrophage activation and m2b polarization. J Immunol. 184:6465–6478. 2010. View Article : Google Scholar : PubMed/NCBI
18	Teachey DT, Seif AE, Brown VI, et al: Targeting notch signaling in autoimmune and lymphoproliferative disease. Blood. 111:705–714. 2008. View Article : Google Scholar
19	Rauen T, Grammatikos AP, Hedrich CM, et al: Camp-responsive element modulator alpha (cremalpha) contributes to decreased notch-1 expression in t cells from patients with active systemic lupus erythematosus (sle). J Biol Chem. 287:42525–42532. 2012. View Article : Google Scholar : PubMed/NCBI
20	Barrat FJ and Coffman RL: Development of tlr inhibitors for the treatment of autoimmune diseases. Immunol Rev. 223:271–283. 2008. View Article : Google Scholar : PubMed/NCBI
21	Comery TA, Martone RL, Aschmies S, et al: Acute gamma-secretase inhibition improves contextual fear conditioning in the tg2576 mouse model of alzheimer’s disease. J Neurosci. 25:8898–8902. 2005. View Article : Google Scholar : PubMed/NCBI
22	Watson ML, Rao JK, Gilkeson GS, et al: Genetic analysis of mrl-lpr mice: Relationship of the fas apoptosis gene to disease manifestations and renal disease-modifying loci. J Exp Med. 176:1645–1656. 1992. View Article : Google Scholar : PubMed/NCBI
23	Takeda K and Akira S: Toll-like receptors in innate immunity. Int Immunol. 17:1–14. 2005. View Article : Google Scholar
24	Roelofs MF, Wenink MH, Brentano F, et al: Type i interferons might form the link between toll-like receptor (tlr) 3/7 and tlr4-mediated synovial inflammation in rheumatoid arthritis (ra). Ann Rheum Dis. 68:1486–1493. 2009. View Article : Google Scholar
25	Marshak-Rothstein A: Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol. 6:823–835. 2006. View Article : Google Scholar : PubMed/NCBI
26	Lyn-Cook BD, Xie C, Oates J, et al: Increased expression of toll-like receptors (tlrs) 7 and 9 and other cytokines in systemic lupus erythematosus (sle) patients: ethnic differences and potential new targets for therapeutic drugs. Mol Immunol. 61:38–43. 2014. View Article : Google Scholar : PubMed/NCBI
27	Ghaly NR, Kotb NA, Nagy HM and Ragehel SM: Toll-like receptor 9 in systemic lupus erythematosus, impact on glucocorticoid treatment. J Dermatolog Treat. 24:411–417. 2013. View Article : Google Scholar
28	Papadimitraki ED, Tzardi M, Bertsias G, et al: Glomerular expression of toll-like receptor-9 in lupus nephritis but not in normal kidneys: Implications for the amplification of the inflammatory response. Lupus. 18:831–835. 2009. View Article : Google Scholar : PubMed/NCBI
29	Guiducci C, Gong M, Xu Z, et al: Tlr recognition of self nucleic acids hampers glucocorticoid activity in lupus. Nature. 465:937–941. 2010. View Article : Google Scholar : PubMed/NCBI
30	Jarrossay D, Napolitani G, Colonna M, et al: Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells. Eur J Immunol. 31:3388–3393. 2001. View Article : Google Scholar : PubMed/NCBI
31	Kadowaki N, Ho S, Antonenko S, et al: Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med. 194:863–869. 2001. View Article : Google Scholar : PubMed/NCBI
32	Dorner M, Brandt S, Tinguely M, et al: Plasma cell toll-like receptor (tlr) expression differs from that of b cells and plasma cell tlr triggering enhances immunoglobulin production. Immunology. 128:573–579. 2009. View Article : Google Scholar : PubMed/NCBI
33	Horton CG, Pan ZJ and Farris AD: Targeting toll-like receptors for treatment of SLE. Mediators Inflamm. 2010:4989802010. View Article : Google Scholar : PubMed/NCBI
34	Harley IT, Kaufman KM, Langefeld CD, et al: Genetic susceptibility to sle: new insights from fine mapping and genome-wide association studies. Nat Rev Genet. 10:285–290. 2009. View Article : Google Scholar : PubMed/NCBI
35	Piotrowski P, Lianeri M, Wudarski M, et al: Contribution of toll-like receptor 9 gene single-nucleotide polymorphism to systemic lupus erythematosus. Rheumatol Int. 33:1121–1125. 2013. View Article : Google Scholar :
36	Mu R, Sun XY, Lim LT, et al: Toll-like receptor 9 is correlated to disease activity in Chinese systemic lupus erythematosus population. Chin Med J (Engl). 125:2873–2877. 2012.
37	Sodsai P, Hirankarn N, Avihingsanon Y, et al: Defects in notch1 upregulation upon activation of t cells from patients with systemic lupus erythematosus are related to lupus disease activity. Lupus. 17:645–653. 2008. View Article : Google Scholar : PubMed/NCBI
38	Henderson L, Masson P, Craig JC, et al: Treatment for lupus nephritis. Cochrane Database Syst Rev. 12:CD0029222012.PubMed/NCBI