Vol 60, No 3 (2022)
Original paper
Published online: 2022-07-06
Celastrol alleviates murine lupus nephritis via inducting CD4+Foxp3+ regulatory T cells
Abstract
Introduction. Lupus nephritis (LN) is an autoimmune glomerulonephritis secondary to systemic lupus erythematosus. Commonly, immunosuppressive agents are required for treating LN. However, frequent use of conventional immunosuppressants may produce a variety of side effects. Hence, seeking alternative drugs for treating LN is very important. This report aims to figure out the immunoregulatory efficacy of celastrol (CLT) in LN.
Material and methods. A spontaneous in vivo model of LN was established in FasL-deficient B6/gld mice. ELISA was used for analyzing serum creatinine (Scr) and anti-dsDNA levels in mice. IHC staining, immunofluorescence and hematoxylin-eosin and PAS staining were applied to determine renal immunopathology and histology. Cytokine gene levels were assessed using RT qPCR. CD4+Foxp3+ Treg frequency in murine kidneys, lymph nodes and spleens was determined using flow cytometry analysis.
Results. CLT treatment alleviated renal dysfunction and renal injury in LN-prone B6/gld mice. Moreover, CLT reduced CD3+ T cell infiltration and inhibited proinflammatory cytokine expression in renal tissues of B6/gld mice. Importantly, CLT enhanced CD4+FoxP3+ Treg frequency in kidneys, lymph nodes and spleens of B6/gld mice.
Conclusions. CLT exerts therapeutic effects on murine LN by improving renal function and immunopathology and inducing CD4+FoxP3+ Tregs.
Keywords: B6/gld micelupus nephritiscelastrolCD4+FoxP3+ cellskidney damagecytokine gene expression
References
- Kiriakidou M, Ching CL. Systemic lupus erythematosus. Ann Intern Med. 2020; 172(11): ITC81–ITC96.
- Chang A, Clark MR, Ko K. Cellular aspects of the pathogenesis of lupus nephritis. Curr Opin Rheumatol. 2021; 33(2): 197–204.
- Aljaberi N, Bennett M, Brunner HI, et al. Proteomic profiling of urine: implications for lupus nephritis. Expert Rev Proteomics. 2019; 16(4): 303–313.
- Ma HY, Chen S, Cao WD, et al. Diagnostic value of TWEAK for predicting active lupus nephritis in patients with systemic lupus erythematosus: a systematic review and meta-analysis. Ren Fail. 2021; 43(1): 20–31.
- Zhao Y, Hu W, Chen P, et al. Immunosuppressive and metabolic agents that influence allo- and xenograft survival by in vivo expansion of T regulatory cells. Xenotransplantation. 2020; 27(6): e12640.
- Xia Y, Fang X, Dai X, et al. Iguratimod ameliorates nephritis by modulating the Th17/Treg paradigm in pristane-induced lupus. Int Immunopharmacol. 2021; 96: 107563.
- Zhao M, Shao Y, Xu J, et al. LINC00466 impacts cell proliferation, metastasis and sensitivity to temozolomide of glioma by sponging miR-137 to regulate PPP1R14B expression. Onco Targets Ther. 2021; 14: 1147–1159.
- Aziz F, Chaudhary K. Lupus nephritis: a treatment update. Curr Clin Pharmacol. 2018; 13(1): 4–13.
- Allison AC, Cacabelos R, Lombardi VR, et al. Celastrol, a potent antioxidant and anti-inflammatory drug, as a possible treatment for Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry. 2001; 25(7): 1341–1357.
- Venkatesha SH, Yu H, Rajaiah R, et al. Celastrus-derived celastrol suppresses autoimmune arthritis by modulating antigen-induced cellular and humoral effector responses. J Biol Chem. 2011; 286(17): 15138–15146.
- Lee JH, Choi KJ, Seo WD, et al. Enhancement of radiation sensitivity in lung cancer cells by celastrol is mediated by inhibition of Hsp90. Int J Mol Med. 2011; 27(3): 441–446.
- Zhang X, Yang J, Chen M, et al. Metabolomics profiles delineate uridine deficiency contributes to mitochondria-mediated apoptosis induced by celastrol in human acute promyelocytic leukemia cells. Oncotarget. 2016; 7(29): 46557–46572.
- Shaker ME, Ashamallah SA, Houssen ME. Celastrol ameliorates murine colitis via modulating oxidative stress, inflammatory cytokines and intestinal homeostasis. Chem Biol Interact. 2014; 210: 26–33.
- Venkatesha SH, Dudics S, Astry B, et al. Control of autoimmune inflammation by celastrol, a natural triterpenoid. Pathog Dis. 2016; 74(6).
- Guo L, Luo S, Du Z, et al. Targeted delivery of celastrol to mesangial cells is effective against mesangioproliferative glomerulonephritis. Nat Commun. 2017; 8(1): 878.
- Xu X, Zhong J, Wu Z, et al. Effects of tripterine on mRNA expression of TGF-beta1 and collagen IV expression in BW F1 mice. Cell Biochem Funct. 2007; 25(5): 501–507.
- Li H, Zhang Yy, Huang XY, et al. Beneficial effect of tripterine on systemic lupus erythematosus induced by active chromatin in BALB/c mice. Eur J Pharmacol. 2005; 512(2-3): 231–237.
- Chu C, He W, Kuang Y, et al. Celastrol protects kidney against ischemia-reperfusion-induced injury in rats. J Surg Res. 2014; 186(1): 398–407.
- Zhang J, Shan J, Chen X, et al. Celastrol mediates Th17 and Treg cell generation via metabolic signaling. Biochem Biophys Res Commun. 2018; 497(3): 883–889.
- Wang Y, Cao Lu, Xu LM, et al. Celastrol ameliorates EAE induction by suppressing pathogenic T cell responses in the peripheral and central nervous systems. J Neuroimmune Pharmacol. 2015; 10(3): 506–516.
- Astry B, Venkatesha SH, Laurence A, et al. Celastrol, a Chinese herbal compound, controls autoimmune inflammation by altering the balance of pathogenic and regulatory T cells in the target organ. Clin Immunol. 2015; 157(2): 228–238.
- Takahashi T, Tanaka M, Brannan CI, et al. Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell. 1994; 76(6): 969–976.
- Liang CL, Lu W, Zhou JY, et al. Mangiferin attenuates murine lupus nephritis by inducing CD4+Foxp3+ regulatory T cells via suppression of mTOR signaling. Cell Physiol Biochem. 2018; 50(4): 1560–1573.
- Costa-Bauza A, Grases F, Gomila I, et al. A simple and rapid colorimetric method for determination of phytate in urine. Urol Res. 2012; 40(6): 663–669.
- Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001; 25(4): 402–408.
- Martin-Moreno PL, Tripathi S, Chandraker A. Regulatory T cells and kidney transplantation. Clin J Am Soc Nephrol. 2018; 13(11): 1760–1764.
- Hou X, Song J, Su J, et al. CD4(+)Foxp3(+) Tregs protect against innate immune cell-mediated fulminant hepatitis in mice. Mol Immunol. 2015; 63(2): 420–427.
- Kronbichler A, Brezina B, Gauckler P, et al. Refractory lupus nephritis: When, why and how to treat. Autoimmun Rev. 2019; 18(5): 510–518.
- Wang S, Chen D, Zuo Ke, et al. Long-term renal outcomes of mesangial proliferative lupus nephritis in Chinese patients. Clin Rheumatol. 2022; 41(2): 429–436.
- Chen J, Wu W, Zhang M, et al. Taraxasterol suppresses inflammation in IL-1β-induced rheumatoid arthritis fibroblast-like synoviocytes and rheumatoid arthritis progression in mice. Int Immunopharmacol. 2019; 70: 274–283.
- Zhao P, Su G, Xiao X, et al. Chinese medicinal herb Radix Astragali suppresses cardiac contractile dysfunction and inflammation in a rat model of autoimmune myocarditis. Toxicol Lett. 2008; 182(1-3): 29–35.
- Luo Y, Zhang Y, Kuai Le, et al. Efficacy and safety of Tripterygium glycosides in Sjögren's syndrome treatment: evidence from 12 randomized controlled trials. Ann Palliat Med. 2021; 10(7): 8215–8231.
- An L, Li Z, Shi L, et al. Inflammation-targeted celastrol nanodrug attenuates collagen-induced arthritis through nf-κb and notch1 pathways. Nano Lett. 2020; 20(10): 7728–7736.
- Liu Y, Xiao N, Du H, et al. Celastrol ameliorates autoimmune disorders in Trex1-deficient mice. Biochem Pharmacol. 2020; 178: 114090.
- Lu Y, Liu Y, Zhou J, et al. Biosynthesis, total synthesis, structural modifications, bioactivity, and mechanism of action of the quinone-methide triterpenoid celastrol. Med Res Rev. 2021; 41(2): 1022–1060.
- Lagoa R, Silva J, Rodrigues JR, et al. Advances in phytochemical delivery systems for improved anticancer activity. Biotechnol Adv. 2020; 38: 107382.
- Abdin AA, Hasby EA. Modulatory effect of celastrol on Th1/Th2 cytokines profile, TLR2 and CD3+ T-lymphocyte expression in a relapsing-remitting model of multiple sclerosis in rats. Eur J Pharmacol. 2014; 742: 102–112.
- Yang H, Liu C, Jiang J, et al. Celastrol attenuates multiple sclerosis and optic neuritis in an experimental autoimmune encephalomyelitis model. Front Pharmacol. 2017; 8: 44.
- Qi WH, Zhang YY, Xing K, et al. 2', 4'-Dihydroxy-2,3-dimethoxychalcone: A pharmacological inverse agonist of RORγt ameliorating Th17-driven inflammatory diseases by regulating Th17/Treg. Int Immunopharmacol. 2022; 108: 108769.
- Honda M, Segawa T, Ishikawa K, et al. Nephronectin influences EAE development by regulating the Th17/Treg balance via reactive oxygen species. Am J Physiol Cell Physiol. 2022; 322(4): C699–C711.
- Zhou F, Wang X, Wang L, et al. Genetics, epigenetics, cellular immunology, and gut microbiota: emerging links with graves' disease. Front Cell Dev Biol. 2021; 9: 794912.
- Nie Y, Fu C, Zhang H, et al. Celastrol slows the progression of early diabetic nephropathy in rats via the PI3K/AKT pathway. BMC Complement Med Ther. 2020; 20(1): 321.
- Hu X, Jia M, Fu Yu, et al. Novel low-toxic derivative of celastrol maintains protective effect against acute renal injury. ACS Omega. 2018; 3(3): 2652–2660.
- Alahyari S, Rajaeinejad M, Jalaeikhoo H, et al. Regulatory T cells in immunopathogenesis and severity of COVID-19: a systematic review. Arch Iran Med. 2022; 25(2): 127–132.
- Esensten JH, Muller YD, Bluestone JA, et al. Regulatory T-cell therapy for autoimmune and autoinflammatory diseases: the next frontier. J Allergy Clin Immunol. 2018; 142(6): 1710–1718.
- Yan JJ, Lee JG, Jang JY, et al. IL-2/anti-IL-2 complexes ameliorate lupus nephritis by expansion of CD4CD25Foxp3 regulatory T cells. Kidney Int. 2017; 91(3): 603–615.
- Matta MC, Soares DC, Kerstenetzky MS, et al. CD4+CD25 high foxp3+ treg deficiency in a Brazilian patient with gaucher disease and lupus nephritis. Hum Immunol. 2016; 77(2): 196–200.
- Afeltra A, Gigante A, Margiotta DP, et al. The involvement of T regulatory lymphocytes in a cohort of lupus nephritis patients: a pilot study. Intern Emerg Med. 2015; 10(6): 677–683.
- Liang CL, Lu W, Qiu F, et al. Paeoniflorin ameliorates murine lupus nephritis by increasing CD4+Foxp3+ Treg cells via enhancing mTNFα-TNFR2 pathway. Biochem Pharmacol. 2021; 185: 114434.
