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).
Recent studies report that VIP reduces the development and severity of experimental arthritis and modulates Th17 cell activity (Delgado M et al., 2001; J Leceta et al., 2007).
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
Updates
A 2018 review by Raúl Villanueva-Romero et al. summarizes the effects of the vasoactive intestinal peptide (VIP) as a homeostatic and immunoregulatory peptide involved in the control of both innate and adaptive immune response. The neuropeptide is acting locally or systematically as it is produced by sympathetic nerve endings, lymphocytes, or even fibroblast-like synoviocytes (FLS) in the joint.
In human RA pathology, VIP acts as anti-inflammatory peptide in synovial tissue cells and FLS from RA patients, where VIP downregulates chemokine and IL-6 production. In FLS, VIP decreases IL-22-specific receptor and prevents the contribution of rheumatoid synovial fibroblasts to IL-22-mediated joint destruction.
The authors discuss their results with activated/expanded memory Th cell “ex vivo” from early RA patients that showed that these cells generate a greater proportion of Th17 cells with pathogenic Th17 and Th17/1 profile. VIP lowered this pathogenic profile, decreasing IL-22, GM-CSF, IL-2, IL-21, IL-23R, IL-21R, T-bet, and STAT3. These results are in agreement with the fact that VIP maintains the nonpathogenic profile of human Th17 polarized cells, decreasing their Th1 potential.
Indeed, VIP inhibits Th17 polarization bias to Th1-like cells, inducing a negative correlation between the master regulators for Th1 and Th17 subsets, Tbx21 (T-bet), and RORC (RORγt), respectively. This suggests that VIP reduces the pathogenic profile of Th17-polarized cells from early RA patients, increasing Treg/Th17 profile and decreasing Th17/Th1 profile.
Moreover, VIP modulates the imbalance between Th subsets in RA, decreasing pathogenic Th1 and Th17 subsets and favoring Th2 or Treg profile during the differentiation/polarization of naïve or memory Th cells.
A 2019 review by Rosa P Gomariz et al. provides an overview of VPAC receptors in rheumatoid arthritis. Thus, Vasoactive Intestinal Peptide (VIP) and its G protein-coupled receptors (GPCRs), VPAC1, and VPAC2, belong to the B1 family and signal through Gs or Gq proteins. VPAC receptors seem to preferentially interact with Gs in inflammatory cells, rather than Gq, thereby stimulating adenylate cyclase activity.
In inflammatory cells, VPAC have greater affinity for Gαs than Gαq, indicating that VPAC receptors preferentially stimulate adenylyl cyclase activity. In the animal model of RA, the CIA model, VIP is able to rebalance Th1/Th2 subsets in the immune system, decreasing Th1 cells and increasing Th2 cells, and to downregulate Th17 responses.
In peripheral blood lymphocytes of RA patients cultured ex vivo, VIP favors the Th2/Treg profile. In addition, VIP reduces the Th17 and Th17/1 pathogen profile of memory Th cells of early RA patients activated/expanded ex vivo. Receptor signaling also downregulates coagulation factors and acute-phase proteins, promotes Th2 over Th1, stimulates Treg abundance, and finally inhibits a pathogenic Th17 profile.
In addition, the differentiation/polarization of Th cells also induces changes in the expression of VPAC receptors; for example, the differentiation/polarization toward Th17 profile induces an increase in the VPAC2/VPAC1 ratio, for example, 18-fold in Th17-differentiated cells from naïve Th cells. During the process of differentiation toward a non-pathogenic Th17 profile, VPAC receptors have shown different roles in regulating the production of inflammatory mediators.
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