Norepinephrine through β2-adrenoceptor activation down-regulates pro-inflammatory pathogenic Th17 cells in a rodent model of rheumatoid arthritis

Norepinephrine through β2-adrenoceptor activation down-regulates pro-inflammatory pathogenic Th17 cells in a rodent model of rheumatoid arthritis

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A recent study in Medical Science Monitor indicates that norepinephrine (noradrenaline), the major sympathetic nervous system neurotransmitter, through stimulation of β2-adrenoceptors (AR) is able to suppress the highly pathogenic T helper 17 (Th17) cells and exert anti-inflammatory effects in a mouse model of arthritis.

In 1986 Mosman et al. discovered the Th1 (mostly pro-inflammatory) and Th2 cells (mostly anti-inflammatory) subsets of CD4+ T lymphocytes. About 20 years later, a third Th cell subset called Th17, and producing the cytokine IL-17 (IL-17A) was found. Th17 cells also produce the cytokines IL-17F, IL-22 and GM-CSF and are characterized by the expression of the transcription factor RORγt. Importantly, Th17 cells are the major players in the development and progression of many inflammatory and autoimmune diseases. This includes rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic lupus erythematosus and multiple sclerosis.

Now is also known that catecholamines (norepinephrine and epinephrine) inhibit the production of Th1/pro-inflammatory, but stimulate the production of Th2/anti-inflammatory cytokines. Thus, sympathetic neuromediators and hormones mediate a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity. However, little is known about the effect of catecholamines on Th17 cell functions.

In rheumatoid arthritis, it appears that there is a defect of the systemic anti-inflammatory feedback systems, and locally sympathetic nerve fibers are markedly reduced in the synovial tissue of patients with RA, in contrast to the pro-inflammatory sensory fibers. Likewise, the sympathetic nerve fibers are also reduced in synovial tissue and lymph nodes of animals with collagen-induced arthritis (CIA).

In the Medical Science Monitor study, Yan Liu and colleagues from the Nantong University, Nantong, Jiangsu, China investigated the expression of β2-AR by CD4+ T cells and the effects of norepinephrine on the Th17 cell differentiation and function in the mouse CIA model of rheumatoid arthritis.

The researchers found that CD4+ T cells expressed β2-AR, and the expression was downregulated during the CIA disease progression. It is known that naive CD4+ T cells and effector Th1 (but not Th2) cells express β2-ARs. Here, Liu et al. provide evidence that β2-ARs are also expressed on Th17 cells, and that this expression is reduced by the CIA condition.

While, the CIA disease model induced an increase of IL-17 and IL-22 production, CD25–IL-17+ cell percentage, and the ROR-γt expression in CD4+ T cells, norepinephrine reduced the T cell shift towards Th17 phenotype and a β2-ARs antagonist reversed this effect.

Importantly, the β2-AR agonist terbutaline inhibited the CIA-induced IL-17 and IL-22 expression, and the expression of the Th17 cell-specific transcriptional factor ROR-γt. Terbutaline also reduced the CIA-induced CD4+ T cell proliferation and the shift towards Th17 phenotype though a protein kinase A (PKA)-dependant pathway.

Overall, these results indicate that the sympathetic nervous system neuromediator norepinephrine, though activation of the β2-AR/PKA pathway is able to down-regulate the development and activity of Th17 cells, and thus, in turn to exert anti-inflammatory effects in the mouse CIA arthritis model.

This may also suggest that β2-adrenoceptor agonists hold a theurapeutic potential in rheumatoid arthritis.

Source: Med Sci Monit, 2018, 24:1196-1204.
Read More: Med Sci Monit

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