Artesunate attenuating intestinal mucosal barrier injury in acute graft-versus-host disease mice

doi:10.16098/j.issn.0529-1356.2025.05.008

PDF(8389 KB)

Acta Anatomica Sinica ›› 2025, Vol. 56 ›› Issue (5) : 566-575. DOI: 10.16098/j.issn.0529-1356.2025.05.008

Cell and Molecules Biology

Artesunate attenuating intestinal mucosal barrier injury in acute graft-versus-host disease mice

KANG Jing¹ CHENG Xu¹ ZHENG Jin-miao¹ LI Yu-xue¹ HAN Li-zhuang^1,2* YANG Shu^1*

Author information +

History +

Abstract

Objective To investigate the mechanism by which artesunate (ART) attenuates intestinal mucosal barrier damage in acute graft-versus-host disease (aGVHD) and the synergistic effect of ART in combination with dexamethasone (DXM) in the treatment of aGVHD mice. Methods The aGVHD mouse model was established by bone marrow haematopoietic stem cell transplantation. The mice were divided into 9 groups, including normal mice control (Ctrl), aGVHD mice (aGVHD), normal mice receiving ART ［30 mg/(kg·d)］, aGVHD mice receiving low-dose ART［10 mg/(kg·d)］, aGVHD mice receiving medium-dose ART ［30 mg/(kg·d)］, aGVHD mice receiving high-dose ART ［50 mg/(kg·d)］, aGVHD mice receiving DXM［20 mg/(kg·d)］, aGVHD mice receiving ART［30 mg /(kg·d)］and DXM ［20 mg/(kg·d)］, and aGVHD mice receiving ART ［30 mg /(kg·d)］ and halved-DXM ［10 mg/(kg·d)］. Survival rate and clinical parameters were assessed. HE staining and Alcian blue-periodic acid-Schiff (AB-PAS) staining were used to observe the histopathological changes in the intestinal mucosa of the mice; Real-time PCR, Western blotting and immunohistochemistry were used to detect the structure of the intestinal mucosal barrier, the T cell differentiation related transcription factors and cytokines, and the key enzymes of energy metabolism. Flow cytometry was used to detect the T helper cell 17(Th17) and regulatory T cells(Treg). Results After 30 days of ART treatment, aGVHD mice showed significant relief of systemic symptoms and increase in survival rate. In aGVHD mice treated with ART, the intestinal mucosal barrier structure was restored, and the intestinal mucosal permeability was reduced. The activity of AMP-activated protein kinase (AMPK)/mTOR pathway was inhibited, and the energy metabolism pattern of T cells was dominated by fatty acid synthesis. The balance of Th17/Treg was restored due to the decrease of Th17 and the increase of Treg. The effect of ART+DXM treatment on aGVHD mice was comparable to that of DXM treatment alone, and the survival rate of mice was higher. In particular, the recovery of the intestinal mucosal barrier function was most obvious in the mice treated with ART + half-dose DXM. Conclusion ART reduces the immune injury of allo-T cells to the intestinal mucosal barrier by recovering the Th17/Treg balance, thus maintaining the integrity of the intestinal mucosal barrier function. The synergistic effect of ART and DXM combination treatment in aGVHD mice can reduce the incidence of DXM side effects by decreasing the dosage of DXM.

Key words

Artesunate / Acute graft-versus-host disease / Intestinal mucosal barrier / T helper cell 17/regulatory T cell balance / Bone marrow transplantation / Flow cytometry / Immunohistochemistry / Mouse

Cite this article

EndNote

Ris (Procite)

Bibtex

Download Citations

KANG Jing CHENG Xu ZHENG Jin-miao LI Yu-xue HAN Li-zhuang YANG Shu. Artesunate attenuating intestinal mucosal barrier injury in acute graft-versus-host disease mice[J]. Acta Anatomica Sinica. 2025, 56(5): 566-575 https://doi.org/10.16098/j.issn.0529-1356.2025.05.008

References

［1］ Wang X, Huang R, Zhang X, et al. Current status and prospects of hematopoietic stem cell transplantation in China［J］. Chin Med J (Engl), 2022, 135(12): 1394-1403.

［2］ Iida M, Dodds A, Akter M, et al. The 2016 APBMT activity survey report: trends in haploidentical and cord blood transplantation in the AsiaPacific region［J］. Blood Cell Ther, 2021, 4(2): 20-28.

［3］ Ghimire S, Weber D, Mavin E, et al. Pathophysiology of GvHD and other HSCT-related major complications［J］. Front Immunol, 2017, 8: 79.

［4］ Malard F, Holler E, Sandmaier BM, et al. Acute graft-versus-host disease［J］. Nat Rev Dis Primers, 2023, 9(1): 27.

［5］ Ramachandran V, Kolli SS, Strowd LC. Review of graft-versus-host disease［J］. Dermatol Clin, 2019, 37(4): 569-582.

［6］ Thiagarajan S, Neurath MF, Hildner K. Resolution of acute intestinal graft-versus-host disease［J］. Semin Immunopathol, 2019, 41(6): 655-664.

［7］ Fletcher RE, Nunes NS, Patterson MT, et al. Posttransplantation cyclophosphamide expands functional myeloid-derived suppressor cells and indirectly influences Tregs［J］. Blood Advances, 2023, 7(7): 1117-1129.

［8］ Wu D, Zhang M, He PCh, et al. Artesunate attenuate chronic graft-versus-host disease by regulating Th17/Treg balance［J］. Journal of Nanjing Medical University (Natural Sciences), 2007, (2): 122-125. (in Chinese)

吴迪, 张梅, 贺鹏程, 等. 小鼠脾细胞在混合骨髓移植中的作用［J］.南京医科大学学报（自然科学版）, 2007, (2): 122-125.

［9］ Ye Y, Ricard L, Stocker N, et al. A novel mouse model of acute graft-versus-host disease based on chemotherapy conditioning and G-CSF mobilized graft［J］. Bone Marrow Transplant, 2020, 55(3): 570-577.

［10］ Noth R, Lange-Grumfeld J, Stüber E, et al. Increased intestinal permeability and tight junction disruption by altered expression and localization of occludin in a murine graft versus host disease model［J］. BMC Gastroenterol, 2011, 11(1): 109.

［11］ Eriguchi Y, Takashima S, Oka H, et al. Graft-versus-host disease disrupts intestinal microbial ecology by inhibiting Paneth cell production of α-defensins［J］. Blood, 2012, 120(1): 223-231.

［12］ Hanash AM, Dudakov JA, Hua G, et al. Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease［J］. Immunity, 2012, 37(2): 339-350.

［13］ Luo Q, Lin J, Zhang L, et al. The anti-malaria drug artesunate inhibits cigarette smoke and ovalbumin concurrent exposure-induced airway inflammation and might reverse glucocorticoid insensitivity［J］. Int Immunopharmacol, 2015, 29(2): 235-245.

［14］ Dang W-Z, Li H, Jiang B, et al. Therapeutic effects of artesunate on lupus-prone MRL/lpr mice are dependent on T follicular helper cell differentiation and activation of JAK2-STAT3 signaling pathway［J］. Phytomedicine, 2019, 62: 152965.

［15］ Yin S, Yang H, Tao Y, et al. Artesunate ameliorates DSS-induced ulcerative colitis by protecting intestinal barrier and inhibiting inflammatory response［J］. Inflammation, 2020, 43(2): 765-776.

［16］ Chen H, Sun H, Wu B, et al. Artesunate delays the dysfunction of age-related intestinal epithelial barrier by mitigating endoplasmic reticulum stress/unfolded protein response［J］. Mech Ageing Dev, 2023, 210: 111760.

［17］ Bai XY, Liu P, Chai YW, et al. Artesunate attenuates 2, 4-dinitrochlorobenzene-induced atopic dermatitis by down-regulating Th17 cell responses in BALB/c mice［J］. Eur J Pharmacol, 2020, 874: 173020.

［18］ Liu J, Hong X, Lin D, et al. Artesunate influences Th17/Treg lymphocyte balance by modulating Treg apoptosis and Th17 proliferation in a murine model of rheumatoid arthritis［J］. Exp The Med, 2017, 13(5): 2267-2273.

［19］ Li Z, Shi X, Liu J, et al. Artesunate prevents type 1 diabetes in NOD mice mainly by inducing protective IL-4-producing T cells and regulatory T cells［J］. FASEB J, 2019, 33(7): 8241-8248.

［20］ Meng QF, Zhang XX, Zhang Z, et al. Therapeutic potential of artesunate in experimental autoimmune myasthenia gravis by upregulated T regulatory cells and regulation of Th1/Th2 cytokines［J］. Pharmazie, 2018, 73(9): 526-532.

［21］ Mancuso RI, Azambuja JH, Olalla Saad ST. Artesunate strongly modulates myeloid and regulatory T cells to prevent LPS-induced systemic inflammation［J］. Biomed Pharmacother, 2021, 143: 112211.

［22］ Jiang H, Fu D, Bidgoli A, et al. T cell subsets in graft versus host disease and graft versus tumor［J］. Front Immunol, 2021, 12: 761448.

［23］ Chen XM, Du X, Weng JY, et al. Artesunate attenuate chronic graft-versus-host disease by regulating Th17/Treg balance［J］. Zhonghua Xue Ye Xue Za Zhi, 2019, 40(1): 63-68. (in Chinese)

陈晓梅, 杜欣, 翁建宇, 等. 青蒿琥酯调控Th17/Treg平衡抑制慢性移植物抗宿主病的实验研究［J］. 中华血液学杂志, 2019, 40(1): 63-68.

［24］ Herrero-Sánchez MC, Rodríguez-Serrano C, Almeida J, et al. Targeting of PI3K/AKT/mTOR pathway to inhibit T cell activation and prevent graft-versus-host disease development［J］. J Hematol Oncol, 2016, 9(1): 113.

［25］ Thiagarajan S, Neurath MF, Hildner K. Resolution of acute intestinal graft-versus-host disease［J］. Semin Immunopatholy, 2019, 41(6): 655-664.