Background: Recent research in our laboratory shows that CD4+ T cells express the β2 adrenergic receptor (β2-AR), and the sympathetic neurotransmitter norepinephrine regulates the function of T cells via β2-AR signaling. However, the immunoregulatory effect of β2-AR and its related mechanisms on rheumatoid arthritis is unknown. Objective: To explore the effects of β2-AR in collagen-induced arthritis (CIA) on the imbalance of T helper (Th) 17/ regulatory T (Treg) cells. Methods: In DBA1/J mice, collagen type II was injected intradermally at the tail base to prepare the CIA model. The specific β2-AR agonist, terbutaline (TBL), was administered intraperitoneally beginning on day 31 and continuing until day 47 after primary vaccination, twice a day. Magnetic beads were used to sort CD3+ T cells subsets from spleen tissues. Results: In vivo, β2-AR agonist TBL alleviated arthritis symptoms in the CIA mice including histopathology of the ankle joints, four limbs’ arthritis score, the thickness of ankle joints, and rear paws. After TBL treatment, in the ankle joints, the levels of proinflammatory factors (IL-17/22) notably decreased and the levels of immunosuppressive factors (IL-10/TGF-β) significantly increased. In vitro, ROR-γt protein expression, Th17 cell number, mRNA expression and the releasing of IL-17/22 from CD3+ T cells reduced following TBL administration. Moreover, TBL enhanced the anti-inflammatory responses of Treg cells. Conclusion: These results suggest that β2-AR activation exerts anti-inflammatory effects through the amelioration of Th17/Treg imbalance in the CIA disease. |
- Sanders VM. The beta2-adrenergic receptor on T and B lymphocytes: do we understand it yet? Brain Behav Immun. 2012;26: 195-200.
- Lee GR. The balance of Th17 versus Treg cells in autoimmunity. Int J Mol Sci. 2018;19: 730.
- Blake SJ, Teng MW. Role of IL-17 and IL-22 in autoimmunity and cancer. Actas Dermosifiliogr. 2014;105 Suppl 1: 41-50.
- Matsuoka T, Shamji MH, Durham SR. Allergen immunotherapy and tolerance. Allergol Int. 2013;62: 403-413.
- Huang HW, Fang XX, Wang XQ, Peng YP and Qiu YH. Regulation of differentiation and function of helper T cells by lymphocyte-derived catecholamines via alpha1- and beta2-adrenoceptors. Neuroimmunomodulation. 2015;22: 138-151.
- Lorton D and Bellinger DL. Molecular mechanisms underlying beta-adrenergic receptor-mediated cross-talk between sympathetic neurons and immune cells. Int J Mol Sci. 2015;16: 5635-5665.
- Walsh NC and Gravallese EM. Bone loss in inflammatory arthritis: mechanisms and treatment strategies. Curr Opin Rheumatol. 2004;16: 419-427.
- McInnes IB and Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365: 2205-2219.
- Harle P, Mobius D, Carr DJ, Scholmerich J and Straub RH. An opposing time-dependent immune-modulating effect of the sympathetic nervous system conferred by altering the cytokine profile in the local lymph nodes and spleen of mice with type II collagen-induced arthritis. Arthritis Rheum. 2005;52: 1305-1313.
- Weidler C, Holzer C, Harbuz M, Hofbauer R, Angele P, Scholmerich J, et al. Low density of sympathetic nerve fibresfibers and increased density of brain derived neurotrophic factor positive cells in RA synovium. Ann Rheum Dis. 2005;64: 13-20.
- del Rey A, Wolff C, Wildmann J, Randolf A, Hahnel A, O Besedovsky H, et al. Disrupted brain-immune system-joint communication during experimental arthritis. Arthritis Rheum. 2008;58: 3090-3099.
- Miltenburg AM, van Laar JM, de Kuiper R, Daha MR and Breedveld FC. T cells cloned from human rheumatoid synovial membrane functionally represent the Th1 subset. Scand J Immunol. 1992;35: 603-610.
- Aarvak T, Chabaud M, Thoen J, Miossec P and Natvig JB. Changes in the Th1 or Th2 cytokine dominance in the synovium of rheumatoid arthritis (RA): a kinetic study of the Th subsets in one unusual RA patient. Rheumatology (Oxford). 2000;39: 513-522.
- Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005;6: 1123-1132.
- Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6: 1133-1141.
- Tesmer LA, Lundy SK, Sarkar S and Fox DA. Th17 cells in human disease. Immunol Rev. 2008;223: 87-113.
- Leipe J, Grunke M, Dechant C, Reindl C, Kerzendorf U, Schulze-Koops H, et al. Role of Th17 cells in human autoimmune arthritis. Arthritis Rheum. 2010;62: 2876-2885.
- Liu Y, Rui XX, Shi H, Qiu YH and Peng YP. Norepinephrine inhibits Th17 cells via beta2-adrenergic receptor (beta2-AR) signaling in a mouse model of rheumatoid arthritis. Med Sci Monit. 2018;24: 1196-1204.
- Niu Q, Cai B, Huang ZC, Shi YY and Wang LL. Disturbed Th17/Treg balance in patients with rheumatoid arthritis. Rheumatol Int. 2012;32: 2731-2736.
- Wang W, Shao S, Jiao Z, Guo M, Xu H and Wang S. The Th17/Treg imbalance and cytokine environment in peripheral blood of patients with rheumatoid arthritis. Rheumatol Int. 2012;32: 887-893.
- Yi JK, Kim HJ, Yu DH, Park SJ, Shin MJ, Yuh HS, et al. Regulation of inflammatory responses and fibroblast-like synoviocyte apoptosis by calcineurin-binding protein 1 in mice with collagen-induced arthritis. Arthritis Rheum. 2012;64: 2191-2200.
- Lu JH, Liu YQ, Deng QW, Peng YP and Qiu YH. Dopamine D2 receptor is involved in alleviation of type II collagen-induced arthritis in mice. Biomed Res Int. 2015;2015: 496759.
- Livak KJ and Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25: 402-408.
- Parasuraman S, Raveendran R, Kesavan R. Blood sample collection in small laboratory animals. Methods. 2010;1: 87-93.
- Wang XQ, Liu Y, Cai HH, Peng YP and Qiu YH. Expression of tyrosine hydroxylase in CD4+ T cells contributes to alleviation of Th17/Treg imbalance in collagen-induced arthritis. Exp Biol Med. 2016;241: 2094-2103.
- Dong L, Wang X, Tan J, Li H, Qian W, Chen J, et al. Decreased expression of microRNA-21 correlates with the imbalance of Th17 and Treg cells in patients with rheumatoid arthritis. J Cell Mol Med. 2014;18: 2213-2224.
- Samson M, Audia S, Janikashvili N, Ciudad M, Trad M, Fraszczak J, et al. Brief report: inhibition of interleukin-6 function corrects Th17/Treg cell imbalance in patients with rheumatoid arthritis. Arthritis Rheum. 2012;64: 2499-2503.
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