Cannabinoid Receptor 2 Selective Agonist Ameliorates Adjuvant-induced Arthritis by Modulating the Balance Between Treg and Th17 Cells

Overview

Journal Front Pharmacol

Date 2025 Feb 17

PMID 39959429

Authors

Na Tian

Cui Yang

Yu Du

Miao Chen

Bin Li

Dan Li

Sheng-Ming Dai

Affiliations

Soon will be listed here.

Abstract

Background: Adjuvant-induced arthritis (AIA) serves as a classic model for rheumatoid arthritis (RA), typified by inflammatory cell infiltration and joint damage. This study explores the therapeutic efficacy of HU-308, a CB2 receptor-specific agonist, on inflammation and immune balance in AIA.

Methods: AIA was induced in mice by CFA injection. AIA mice were treated with HU-308 or vehicle, and effects on paw swelling, spleen index, histopathology, and immune cell profiles were evaluated. Flow cytometry, differentiation assays, and Western blot analysis were performed to examine Th17 and Treg cells, as well as signaling pathways involved in their differentiation.

Results: HU-308 reduced paw swelling, lowered spleen index, and preserved joint integrity in AIA mice, mitigating inflammatory cell infiltration and bone erosion. Flow cytometry revealed that HU-308 restored the Th17/Treg imbalance in AIA, decreasing Th17 cell frequency and enhancing Treg cell infiltration. assays confirmed HU-308s role in promoting Treg differentiation and inhibiting Th17 polarization. Western blot analysis indicated that HU-308 modulated immune balance through the JAK/STAT5 and TGF-β/SMAD signaling pathways, increasing Foxp3 and TGF-β expression.

Conclusion: HU-308 demonstrates significant anti-inflammatory effects in AIA by restoring Th17/Treg balance and reducing joint damage. The findings indicate that HU-308 holds potential as an immunomodulatory agent for RA, providing valuable insights into CB2-mediated therapeutic strategies for autoimmune diseases.

References

Derynck R, Zhang Y . Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 2003; 425(6958):577-84. DOI: 10.1038/nature02006. View

Jin L, Chen Q, Hu K, Fan D, Zhang H, Deng J . The FTO-CMPK2 Pathway in Fibroblast-like Synoviocytes Modulates Rheumatoid Arthritis Synovial Inflammation and Cartilage Homeostasis via mtDNA Regulation. Int J Biol Sci. 2024; 20(5):1617-1633. PMC: 10929198. DOI: 10.7150/ijbs.90677. View

Jiang Q, Yang G, Liu Q, Wang S, Cui D . Function and Role of Regulatory T Cells in Rheumatoid Arthritis. Front Immunol. 2021; 12:626193. PMC: 8047316. DOI: 10.3389/fimmu.2021.626193. View

van Vollenhoven R . Treatment of rheumatoid arthritis: state of the art 2009. Nat Rev Rheumatol. 2009; 5(10):531-41. DOI: 10.1038/nrrheum.2009.182. View

Fayaz Ahmad S, Attia S, Zoheir K, Ashour A, Bakheet S . Attenuation of the progression of adjuvant-induced arthritis by 3-aminobenzamide treatment. Int Immunopharmacol. 2014; 19(1):52-9. DOI: 10.1016/j.intimp.2014.01.005. View

Feldmann M, Maini R . Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned?. Annu Rev Immunol. 2001; 19:163-96. DOI: 10.1146/annurev.immunol.19.1.163. View

Sarsembayeva A, Kienzl M, Gruden E, Ristic D, Maitz K, Valadez-Cosmes P . Cannabinoid receptor 2 plays a pro-tumorigenic role in non-small cell lung cancer by limiting anti-tumor activity of CD8 T and NK cells. Front Immunol. 2023; 13:997115. PMC: 9868666. DOI: 10.3389/fimmu.2022.997115. View

Xiong X, Chen S, Shen J, You H, Yang H, Yan C . Cannabis suppresses antitumor immunity by inhibiting JAK/STAT signaling in T cells through CNR2. Signal Transduct Target Ther. 2022; 7(1):99. PMC: 8983672. DOI: 10.1038/s41392-022-00918-y. View

Josefowicz S, Lu L, Rudensky A . Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol. 2012; 30:531-64. PMC: 6066374. DOI: 10.1146/annurev.immunol.25.022106.141623. View

10.

Gaffal E, Kemter A, Scheu S, Leite Dantas R, Vogt J, Baune B . Cannabinoid Receptor 2 Modulates Maturation of Dendritic Cells and Their Capacity to Induce Hapten-Induced Contact Hypersensitivity. Int J Mol Sci. 2020; 21(2). PMC: 7013892. DOI: 10.3390/ijms21020475. View

11.

Maresz K, Pryce G, Ponomarev E, Marsicano G, Croxford J, Shriver L . Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells. Nat Med. 2007; 13(4):492-7. DOI: 10.1038/nm1561. View

12.

Miller A, Stella N . CB2 receptor-mediated migration of immune cells: it can go either way. Br J Pharmacol. 2007; 153(2):299-308. PMC: 2219538. DOI: 10.1038/sj.bjp.0707523. View

13.

Cross M, Smith E, Hoy D, Carmona L, Wolfe F, Vos T . The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis. 2014; 73(7):1316-22. DOI: 10.1136/annrheumdis-2013-204627. View

14.

Schmierer B, Hill C . TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol. 2007; 8(12):970-82. DOI: 10.1038/nrm2297. View

15.

Weyand C, Goronzy J . The immunology of rheumatoid arthritis. Nat Immunol. 2020; 22(1):10-18. PMC: 8557973. DOI: 10.1038/s41590-020-00816-x. View

16.

Knochelmann H, Dwyer C, Bailey S, Amaya S, Elston D, Mazza-McCrann J . When worlds collide: Th17 and Treg cells in cancer and autoimmunity. Cell Mol Immunol. 2018; 15(5):458-469. PMC: 6068176. DOI: 10.1038/s41423-018-0004-4. View

17.

Sakaguchi S . Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol. 2005; 6(4):345-52. DOI: 10.1038/ni1178. View

18.

McInnes I, Schett G . The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011; 365(23):2205-19. DOI: 10.1056/NEJMra1004965. View

19.

Yang P, Qian F, Zhang M, Xu A, Wang X, Jiang B . Th17 cell pathogenicity and plasticity in rheumatoid arthritis. J Leukoc Biol. 2019; 106(6):1233-1240. DOI: 10.1002/JLB.4RU0619-197R. View

20.

Kong J, Jeong G, Yoo S . The use of animal models in rheumatoid arthritis research. J Yeungnam Med Sci. 2022; 40(1):23-29. PMC: 9946911. DOI: 10.12701/jyms.2022.00773. View