Vasoactive Intestinal Peptide Inhibits Th17 Cells
A study published by Rebeca Jimeno et al. published in the Journal of Leukocyte Biology indicates that in blood from rheumatoid arthritis (RA) patients, vasoactive intestinal peptide (VIP) shifts the activity of T cells towards a more T regulatory cell phenotype, and reduces the pathogenic profile of T helper (Th)17 cells.
Rheumatoid arthritis is an autoimmune disease that results in chronic inflammation and tissue damage in the joints. T and B cells have been implicated in the pathogenesis of RA. Whereas autoantibodies to Igs and citrullinated peptides play a central role in generating joint-specific inflammation, the role of different autoreactive T cell subsets has been the subject of an intense debate.
Once arthritogenic function was attributed to Th1 cells, the subsequent discovery of the Th17 subset indicated a central role for these cells in this pathology, recently becoming a target for the treatment of the disease.
Thus, recent research points to a central role of Th17 cells in RA pathogenesis, and that these cells are key orchestrators of chronic inflammation in RA. Th17 levels in peripheral blood are associated with disease activity, and IL-17 levels are increased in the synovial fluid of RA patients. IL-17 is a key orchestrator of the chronicity of RA.
Th17 cells have been proposed to include pathogenic and nonpathogenic cells, according to the polarization conditions and the cytokines secreted. Whereas IL-6 is necessary for the development of both cell phenotypes, the presence of TGF-β determines the development of nonpathogenic Th17 cell.
Aside from the phenotypic plasticity of Th17 cells toward a Th1-like condition, the shift to Tregs has been described recently. Indeed, the nonpathogenic phenotype of Th17 cells is more strongly associated with an iTreg profile.
Thus, it is important to understand the regulation of the pathogenicity/plasticity of memory Th17 cells in RA. Of particular importance in this aspect is the influence of an extracellular environment. The neuroendocrine milieu has been suggested as an essential factor conditioning the differentiation of lymphoid cells.
The vasoactive intestinal peptide (VIP) is well-known for its immunoregulatory properties. VIP is one of the best-studied immunoregulatory peptides, modulating innate and adaptive immunity. It functions through binding to its specific receptors VPAC1 and VPAC2.
VIP modulates immune responses, showing a predominantly anti-inflammatory action and a potent immunoregulatory action, by decreasing the Th1/Th2 cytokine ratio. This includes mostly anti-inflammatory actions, induction of Th2 cell polarization, and promotion of T regulatory functions (Ganea D, Gonzalez-Rey E & Delgado M, 2006).
It has been reported that VIP is able to promote the Th17 differentiation from mouse and human Th cells. Additionally, it has been shown that VIP prevents the development of collagen-induced arthritis. In human RA, VIP is present in the microenvironment of the joints, and its therapeutic effects have been supported by several studies. Circulating VIP levels have been described as a prognostic biologic marker, predicting the evolution of eRA patients.
In the Journal of Leukocyte Biology study the authors studied CD4+CD45RO+ T cells from the blood of early RA patients under a Th-17 polarizing environment in the presence of VIP.
They demonstrated that 7 days of co-culture with VIP resulted in reduced levels of IL-22 production, and increased levels of IL-10 and IL-9 in the supernatants of Th cell cultures from early RA patients.
Of note, VIP also increased the levels of Foxp3 RNA expression and the Treg/Th17 ratio.
This study addresses a novel and interesting question on the effect of VIP on the pathogenesis of human Th17 cells and adds clinical relevance to this question by analyzing, in parallel, HD and eRA patients.
In conclusion, the results of this sudy indicate that Th17 cells from eRA patients are prone to expand to a pathologic cell population under Th17-polarizing conditions in the presence of TGF-β and that VIP reduces the pathogenic profile of the Th17 cells in eRA patients and HD
These results indicate that VIP may have promising effects in the early phase of RA targeting the inhibition of pathogenic Th17 cells, and favoring Treg cell differentiation.
Source: Journal of Leukocyte Biology, 2015. DOI: 10.1189/jlb.3A0714-327R
Read more: Journal of Leukocyte Biology
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