Curcumin chitosan microspheres regulate Th17/Treg balance via IGF2BP1- mediated m6A modification of LRP5 in ulcerative colitis

Document Type : Original Article

Authors

1 Traditional Chinese Medicine Department, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, China

2 Anorectal Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China

3 Department of Rehabilitation Medicine, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, China

4 Department of Anesthesiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China

5 Department of Ophthalmology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China

6 Digestive System Department, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China

Abstract

Objective(s): Ulcerative colitis (UC) is a commonly recurrent inflammatory bowel disease. T helper 17 (Th17)/regulatory T (Treg) cell balance plays an essential role in UC progression. However, it is unknown whether curcumin chitosan microspheres (CCM) regulate the Th17/Treg cell balance.
Materials and Methods: The UC mouse model was established by administering 3% dextran sodium sulfate and treated with CCM. The influence of CCM on the Th17/Treg balance was detected using flow cytometry. Cell experiments were conducted to investigate the role and mechanism of IGF2BP1 in Th17/Treg balance.
Results: We revealed that CCM demonstrated a significant therapeutic effect on UC. CCM obviously decreased the Th17 cell percentage but boosted the Treg cell percentage in UC mice. CCM remarkably increased the mRNA expression of Foxp3 but suppressed RORγt and interleukin-10 mRNA expression. PCR array of RNA modification-related genes revealed that the m6A binding protein IGF2BP1 was a key molecule in CCM regulation of Th17/Treg balance. IGF2BP1 overexpression dramatically repressed the CCM-induced balance of Th17/Treg cell differentiation. Mechanically, IGF2BP1 targeted LRP5 and regulated LRP5 through m6A modification. Furthermore, the silencing of LRP5 canceled the suppressive effect of IGF2BP1 on Th17/Treg cell percentage.
Conclusion: CCM modulated the Th17/Treg balance through IGF2BP1-mediated m6A modification, thereby alleviating UC, and providing new ideas for the treatment of UC.

Keywords

Main Subjects

References

1. Xu Y, Zhu BW, Li X, Li YF, Ye XM, Hu JN. Glycogen-based pH and redox sensitive nanoparticles with ginsenoside Rh2 for effective treatment of ulcerative colitis. Biomaterials 2022;280: 121077.
2. George LA, Cross RK. Treatment of ulcerative colitis with steroids (in Whom, How Long, What Dose, What Form). Gastroenterol Clin North Am 2020; 49:705-716.
3. Kobayashi T, Siegmund B, Le Berre C, Wei SC, Ferrante M, Shen B, et al. Ulcerative colitis. Nat Rev Dis Primers 2020; 6:74.
4. Marton LT, Barbalho SM, Sloan KP, Sloan LA, Goulart RA, Araujo AC, et al. Curcumin, autoimmune and inflammatory diseases: going beyond conventional therapy - a systematic review. Crit Rev Food Sci Nutr 2022; 62: 2140-2157.
5. Kang ZP, Wang MX, Wu TT, Liu DY, Wang HY, Long J, et al. Curcumin alleviated dextran sulfate sodium-induced colitis by regulating M1/M2 macrophage polarization and TLRs signaling pathway. Evid Based Complement Alternat Med 2021; 2021:3334994-33341003.
6. Gong Z, Zhao S, Zhou J, Yan J, Wang L, Du X, et al. Curcumin alleviates DSS-induced colitis via inhibiting NLRP3 inflammsome activation and IL-1beta production. Mol Immunol 2018; 104: 11-19.
7. Chen HW, Fang WP. A novel method for the microencapsulation of curcumin by high-pressure processing for enhancing the stability and preservation. Int J Pharm 2022; 613: 121403.
8. Hatamipour M, Sahebkar A, Alavizadeh SH, Dorri M, Jaafari MR. Novel nanomicelle formulation to enhance bioavailability and stability of curcuminoids. Iran J Basic Med Sci 2019; 22: 282-289.
9. Orowitz TE, Ana Sombo P, Rahayu D, Hasanah AN. Microsphere polymers in molecular imprinting: Current and future perspectives. Molecules 2020; 25:3256-3285.
10. Peers S, Montembault A, Ladaviere C. Chitosan hydrogels for sustained drug delivery. J Control Release 2020; 326:150-163.
11. Pramanik S, Sali V. Connecting the dots in drug delivery: A tour d’horizon of chitosan-based nanocarriers system. Int J Biol Macromol 2021; 169:103-121.
12. Saranya TS, Rajan VK, Biswas R, Jayakumar R, Sathianarayanan S. Synthesis, characterisation and biomedical applications of curcumin conjugated chitosan microspheres. Int J Biol Macromol 2018; 110:227-233.
13. Ueno A, Jeffery L, Kobayashi T, Hibi T, Ghosh S, Jijon H. Th17 plasticity and its relevance to inflammatory bowel disease. J Autoimmun 2018; 87:38-49.
14. Yan JB, Luo MM, Chen ZY, He BH. The function and role of the Th17/Treg cell balance in inflammatory bowel disease. J Immunol Res 2020; 2020:8    15. Yasuda K, Takeuchi Y, Hirota K. The pathogenicity of Th17 cells in autoimmune diseases. Semin Immunopathol 2019; 41:283-297.
16. Savage PA, Klawon DEJ, Miller CH. Regulatory T cell development. Annu Rev Immunol 2020; 38: 421-453.
17. Hwang SM, Sharma G, Verma R, Byun S, Rudra D, Im SH. Inflammation-induced Id2 promotes plasticity in regulatory T cells. Nat Commun 2018; 9: 4736-4748.
18. Yu J, Wang S, Yuan H, Qiao T, Bao M. Expression of Th17/Treg cells in peripheral blood and related cytokines of patients with ulcerative colitis of different syndrome types and correlation with the disease. Evid Based Complement Alternat Med 2021; 2021:4600947.
19. Gong Y, Lin Y, Zhao N, He X, Lu A, Wei W, et al. The Th17/Treg immune imbalance in ulcerative colitis disease in a Chinese Han population. Mediators Inflamm 2016; 2016: 7089137-7089142.
20. Zhang C, Ju J, Wu X, Yang J, Yang Q, Liu C, et al. Tripterygium wilfordii polyglycoside ameliorated TNBS-induced colitis in rats via regulating Th17/Treg balance in intestinal mucosa. J Inflamm Res 2021; 14:1243-1255.
21. Dong L, Cao Y, Hou Y, Liu G. N6-methyladenosine RNA methylation: A novel regulator of the development and function of immune cells. J Cell Physiol 2022; 237:329-345.
22. Zhao Y, Shi Y, Shen H, Xie W. m6A-binding proteins: The emerging crucial performers in epigenetics. J Hematol Oncol 2020; 13:35-48.
23. Wang X, Ji Y, Feng P, Liu R, Li G, Zheng J, et al. The m6A reader IGF2BP2 regulates macrophage phenotypic activation and inflammatory diseases by stabilizing TSC1 and PPARgamma. Adv Sci (Weinh) 2021; 8: 2100209-2100222.
24. Lu TX, Zheng Z, Zhang L, Sun HL, Bissonnette M, Huang H, et al. A new model of spontaneous colitis in mice induced by deletion of an RNA m6A methyltransferase component METTL14 in T cells. Cell Mol Gastroenterol Hepatol 2020; 10:747-761.
25. Tong J, Cao G, Zhang T, Sefik E, Amezcua Vesely MC, Broughton JP, et al. m6A mRNA methylation sustains Treg suppressive functions. Cell Res 2018; 28:253-256.
26. Zhou J, Zhang X, Hu J, Qu R, Yu Z, Xu H, et al. m6A demethylase ALKBH5 controls CD4+ T cell pathogenicity and promotes autoimmunity. Sci Adv 2021;7:eabg0470-0484.
27. Dong Y, Fan H, Zhang Z, Jiang F, Li M, Zhou H, et al. Berberine ameliorates DSS-induced intestinal mucosal barrier dysfunction through microbiota-dependence and Wnt/beta-catenin pathway. Int J Biol Sci 2022; 18:1381-1397.
28. Yang J, Liu XX, Fan H, Tang Q, Shou ZX, Zuo DM, et al. Extracellular vesicles derived from bone marrow mesenchymal stem cells protect against experimental colitis via attenuating colon inflammation, oxidative stress and apoptosis. PLoS One 2015; 10:e0140551-140569.
29. Dieleman LA, Ridwan BU, Tennyson GS, Beagley KW, Bucy RP, Elson CO. Dextran sulfate sodium-induced colitis occurs in severe combined immunodeficient mice. Gastroenterology 1994; 107:1643-1652.
30. Zhao G, Liu Y, Yi X, Wang Y, Qiao S, Li Z, et al. Curcumin inhibiting Th17 cell differentiation by regulating the metabotropic glutamate receptor-4 expression on dendritic cells. Int Immunopharmacol 2017; 46: 80-86.
31. Luo Y, Guo J, Zhang P, Cheuk YC, Jiang Y, Wang J, et al. Mesenchymal stem cell protects injured renal tubular epithelial cells by regulating mTOR-mediated Th17/Treg axis. Front Immunol 2021; 12: 684197-684204.
32. Gu D, Nan Q, Miao Y, Yang H, Li M, Ye Y, et al. KT2 alleviates ulcerative colitis by reducing Th17 cell differentiation through the miR-302c-5p/STAT3 axis. Eur J Cell Biol 2022; 101:151223-151233.
33. Yu R, Zuo F, Ma H, Chen S. Exopolysaccharide-producing Bifidobacterium adolescentis strains with similar adhesion property induce differential regulation of inflammatory immune response in Treg/Th17 axis of DSS-colitis mice. Nutrients 2019; 11:782-801.
34. Wang W, Xiang T, Yang Y, Wang Z, Xie J. E3 ubiquitin ligases STUB1 contributes to the Th17/Treg imbalance via the ubiquitination of aryl hydrocarbon receptor in rheumatoid arthritis. Clin Exp Immunol 2022; 209:280-290.
35. Zhang R, Tian A, Wang J, Shen X, Qi G, Tang Y. miR26a modulates Th17/Treg balance in the EAE model of multiple sclerosis by targeting IL6. Neuromolecular Med 2015; 17:24-34.
36. Chang Y, Zhai L, Peng J, Wu H, Bian Z, Xiao H. Phytochemicals as regulators of Th17/Treg balance in inflammatory bowel diseases. Biomed Pharmacother 2021; 141:111931-111946.
37. Zhong Y, Liu W, Xiong Y, Li Y, Wan Q, Zhou W, et al. Astragaloside alleviates ulcerative colitis by regulating the balance of Th17/Treg cells. Phytomedicine 2022; 104:154287.
38. Li Z, Lin M, Li Y, Shao J, Huang R, Qiu Y, et al. Total flavonoids of Sophora flavescens and kurarinone ameliorated ulcerative colitis by regulating Th17/Treg cell homeostasis. J Ethnopharmacol 2022; 297:115500.
39. Wang H, Hu X, Huang M, Liu J, Gu Y, Ma L, et al. Mettl3-mediated mRNA m6A methylation promotes dendritic cell activation. Nat Commun 2019; 10:1898-1909.
40. Li HB, Tong J, Zhu S, Batista PJ, Duffy EE, Zhao J, et al. m6A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways. Nature 2017; 548:338-342.
41. Wang Z, Qi Y, Feng Y, Xu H, Wang J, Zhang L, et al. The N6-methyladenosine writer WTAP contributes to the induction of immune tolerance post kidney transplantation by targeting regulatory T cells. Lab Invest 2022; 102: 1268-1279.
42. Hu S, Chen M, Wang Y, Wang Z, Pei Y, Fan R, et al. mTOR inhibition attenuates dextran sulfate sodium-induced colitis by suppressing T cell proliferation and balancing TH1/TH17/Treg profile. PLoS One 2016; 11:e0154564-154582.
43. Zhang Y, Jing Y, Qiao J, Luan B, Wang X, Wang L, et al. Activation of the mTOR signaling pathway is required for asthma onset. Sci Rep 2017; 7:4532-4544.
Iranian Journal of Basic Medical Sciences
Volume 27, Issue 10
October 2024
Pages 1276-1283

Files

Share

How to cite

Statistics