Abstract
BackgroundAllergic rhinitis (AR) is one of the most widespread immune conditions worldwide. However, common treatments often present with significant side effects or are cost-prohibitive for much of the population. A plethora of treatments have been used for the treatment of AR including antihistamines, steroids, and immune modulators. Among the treatments which have shown potential for efficacy in treating AR with a minimum of side effects but remains understudied is the conditionally essential amino acid taurine. Taurine has been previously shown to reduce AR symptoms. Here, we examine the role of taurine in modulating T regulatory cells, modulating the cytokine response in AR, and restoring healthy nasal mucosa.MethodsBlood samples from 20 healthy donors and 20 AR patients were compared for CD4+CD25+FoxP3+ T regulatory (Treg) cell population percentage, cytokine release, and STAT1 signaling with and without taurine treatment or IL-35 neutralization. An OVA-induced AR mouse model was administered vehicle, taurine, or taurine plus an IL-35 neutralizing antibody and assayed for sneezing frequency, inflammatory cytokine response, nasal mucosa goblet cell density, and T regulatory cell percentage. CD4+ cells were further examined for cytokine release, STAT1 phosphorylation, and response to an anti-IL-35 antibody with and without a STAT1 inhibitor.ResultsComparison of blood from normal donors and AR patients showed a reduction in CD4+CD25+FoxP3+ Treg cells in AR patients and a strong correlation between Treg percentage and IL-35 release. A similar pattern of Treg suppression was found in untreated AR mice when compared to normal control mice wherein there was a reduction in Treg percentage and a corresponding decrease in IL-35 release. AR mice also demonstrated increased sneezing frequency, an infiltration of goblet cell in nasal mucosa, and a reduction in IL-35 release from CD4+ cells. Conversely, IL-4, IL-5, and IL-13 secretion from CD4+ cells were increased in AR model mice, as was STAT1 phosphorylation. When AR mice were treated with taurine, sneezing frequency and nasal mucosa goblet cell content were reduced while Treg abundance was increased to that of normal mice. Accordingly, IL-35 release was restored, while IL-4, IL-5, and IL-13 secretion from CD4+ cells were suppressed. Likewise, STAT1 phosphorylation was inhibited with taurine treatment. Taurine-treated mice also given an IL-35 neutralizing antibody exhibited AR pathology including frequent sneezing and high nasal goblet cell content while retaining a restoration of Tregs. Furthermore, murine AR model CD4+ cells exposed to recombinant IL-35 responded with a reduction in inflammatory cytokine release and a decrease in STAT1 phosphorylation, mimicking the effect of taurine treatment.ConclusionsTaurine induces release of IL-35 in AR; IL-35 promotes the production of CD4+CD25+FoxP3+ Treg cells via a STAT1-dependent pathway. The restoration of Treg populations by taurine normalizes the inflammatory response, reduces AR symptomology, and reduces histopathologic signs of AR.
Highlights
Allergic rhinitis (AR) is one of the most widespread immune conditions worldwide
IL‐35 secretion correlates positively with the percentage of CD4+CD25+Foxp3+ T regulatory (Treg) cells in the blood of patients with allergic rhinitis (AR) PBMCs were isolated from whole blood of patients with AR or from healthy controls and magnetically sorted for CD4 expression followed Forkhead Box P3 (FoxP3) and CD25 quantification by flow cytometry to identify Tregs. CD25+/FoxP3+ cells were significantly less abundant in AR patients when compared to normal controls (2.5 vs 7%); interestingly the reduction in doublepositive cells can be accounted for by the loss of FoxP3 expression alone (Fig. 1A)
IL-35 secretion from cultured PBMCs isolated from AR patients was significantly reduced compared to that from that secreted by PBMCs isolated from healthy controls, as measured by ELISA (Fig. 1B, left)
Summary
Allergic rhinitis (AR) is one of the most widespread immune conditions worldwide. common treatments often present with significant side effects or are cost-prohibitive for much of the population. Methods: Blood samples from 20 healthy donors and 20 AR patients were compared for C D4+CD25+FoxP3+ T regulatory (Treg) cell population percentage, cytokine release, and STAT1 signaling with and without taurine treatment or IL-35 neutralization. When AR mice were treated with taurine, sneezing frequency and nasal mucosa goblet cell content were reduced while Treg abundance was increased to that of normal mice. Taurine-treated mice given an IL-35 neutralizing antibody exhibited AR pathology including frequent sneezing and high nasal goblet cell content while retaining a restoration of Tregs. Allergic rhinitis (AR) is a very common condition with approximately 10–40% people affected globally [1] and is the most widespread chronic disease in children [2], which is manifested by nasal congestion and excessive mucus production, results from a misdirection of the immune system towards non-pathogenic antigens. Regardless, there are no treatments which are universally effective and there remains a clear need for an efficacious AR treatment with a highly tolerable side effect profile
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