Taurine Promotes the Production of CD4+CD25+FOXP3+ Treg Cells through Regulating IL-35/STAT1 Pathway in a Mouse Allergic Rhinitis Model

Abstract

Background: Allergic 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.Methods: Blood 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. Results: Comparison 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. Conclusions: Taurine 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.

Perspectives of herbs and their natural compounds, and herb formulas on treating diverse diseases through regulating complicated JAK/STAT signaling

“…Regarding the aspects of Chinese herbal formulas, approximately five herbal formulas regulating STAT1 cascade were collected in preclinical investigational studies, and these were Yu-Ping-Feng decoction (Zhou et al, 2021), Yiguanjian decoction (Boriero et al, 2021), Sijunzi decoction (Xiong and Qian, 2013), Yu-Ping-Feng powder (Xiong and Qian, 2013), Ganghuo Kanggan decoction (Lai et al, 2020), and Xin-Jia-Xiang-Ru-Yin (Li et al, 2018). These formulas, Yiguanjian decoction (Boriero et al, 2021), Sijunzi decoction (Xiong and Qian, 2013), Yupingfeng powder (Lai et al, 2020), Ganghuo Kanggan decoction (Lai et al, 2020), and Xin-Jia-Xiang-Ru-Yin (Li et al, 2018), were crucial for treating hepatic fibrosis, spleen deficiency, and influenza through inhibiting STAT1 signaling, whereas the other formula, Yu-Ping-Feng decoction, induces opposite effects on STAT1 activation to anti-cancer (Zhou et al, 2021). Extracts from two herbs, including a natural extract from Gardenia jasminoides J. Ellis (GJ-4) (Liu et al, 2021) and bisabolane-type sesquiterpenoids isolated from turmeric (Ti et al, 2021), were mentioned here to antagonize Alzheimer's disease (AD) and infection through inactivating STAT1.…”

“…Extracts from two herbs, including a natural extract from Gardenia jasminoides J. Ellis (GJ-4) (Liu et al, 2021) and bisabolane-type sesquiterpenoids isolated from turmeric (Ti et al, 2021), were mentioned here to antagonize Alzheimer's disease (AD) and infection through inactivating STAT1. Correspondingly, about nine natural compounds and phytochemicals isolated from herbs and plants exhibited good performance in anti-cancer (Liang et al, 2021a;Jiang et al, 2022), treating allergic rhinitis (Zhou et al, 2021), MS (Du et al, 2021a), nonalcoholic steatohepatitis (Luo et al, 2021b), anti-depression (Zheng et al, 2021) and promoting skin-moisturizing activities (Chen et al, 2021b), acute lower respiratory tract infection (Wang et al, 2020a), renal inflammatory injury (Hu et al, 2020), and ischemic cerebrovascular diseases (Boriero et al, 2021) through influencing STAT1 signaling. Natural compounds' combined utilization has been increasingly popular in recent years for their decrease of deficiencies and complementary advantages.…”

“…TS IIA and AS IV and TS IIA and Puerarin were presented here for their excellent performance in protecting against lumbar intervertebral disc degeneration (Du et al, 2021b) and idiopathic pulmonary fibrosis (IPF) (Xue et al, 2021) through restricting STAT1 cascade via combined utilization. As mentioned above, potential candidates, including baicalin (Jiang et al, 2022), dihydroartemisinin (Du et al, 2021a), kahweol (Chen et al, 2021b), and Yu-Ping-Feng decoction (Zhou et al, 2021), exerted their anti-cancer and antiinfection properties through upregulating cell apoptosis and reinforcing immune system via activating STAT1 signaling, which caused high levels of apoptotic proteins, that is, caspases and enhanced the expression of immune cells, such as T cells and B cells. Conversely, compounds effectively treated allergic rhinitis (Zhou et al, 2021) and influenza (Ti et al, 2021) through inhibiting STAT1 signaling, reducing the expression of inflammatory mediators, and regulating cell differentiation.…”

“…In addition, dihydroartemisinin ameliorated multiple sclerosis (Du et al, 2021a) and gastric cancer (Liang et al, 2021a) through regulating STAT1 signaling. Moreover, Yu-Ping-Feng decoction (Boriero et al, 2021;Zhou et al, 2021), Sijunzi decoction (Xiong and Qian, 2013), and Yu-Ping-Feng powder (Xiong and Qian, 2013) exerted their effects on anti-NSCLC and spleen deficiency through influencing STAT1 signaling. Meanwhile, we also summarized the candidates for treating diverse diseases involved in JAK/STAT signaling, such as anticancer, ameliorating inflammation, allergic asthma, chronic kidney disease, rheumatoid arthritis, and fibrosis.…”

The role of IL-35 and IL-37 in breast cancer – potential therapeutic targets for precision medicine

“…However, it has been reported that some TILs, e.g. T regulatory (Treg) cells, which are CD4 + /CD25 + , are able to regulate host immunity via the IL-35 signalling pathway (13), which may contribute to immune escape of malignant cells.…”