Hongbing Yao

An aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress the Th17 response in allergic rhinitis patients.

A predominant Th17 population is a marker of allergic rhinitis (AR). The aryl hydrocarbon receptor (AhR) exhibits strong immunomodulation potential via regulation of the differentiation of T lymphocytes and dendritic cells (DCs) after activation by its ligand, such as 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). The aim of this study was to analyze the effect of AhR on Th17 differentiation by investigating the action of ITE on DCs and CD4+ T cells from patients with AR. In all, 26 AR patients and 12 healthy controls were included in this study. The expression of interleukin (IL)-1β, IL-6, IL-10, and IL-17 in the culture supernatant and the presence of Th17 cells in CD4+ T cells and DC–CD4+ T-cell co-culture system were measured before and after treatment with ITE. We show that ITE significantly induced cell secretion of IL-10 and inhibited IL-1β and IL-6 production in DCs, and promoted IL-10 production and suppressed IL-17 expression in CD4+ T cells in vitro. It also suppressed the expansion of Th17 cells in vitro. Our work demonstrates that ITE acts on DCs and CD4+ T cells to inhibit the Th17 response that suppresses AR; the AhR–DC–Th17 axis may be an important pathway in the treatment of AR. ITE, a nontoxic AhR ligand, attenuated the Th17 response; thus, it appears to be a promising therapeutic candidate for suppressing the inflammatory responses associated with AR.

Regulation of Transforming Growth Factor-β1 Activation and Expression in the Tissue Remodeling Involved in Chronic Rhinosinusitis

Transforming growth factor-β1 (TGF-β1) plays a key role in the tissue remodeling processes involved in chronic rhinosinusitis (CRS), with the biological functions of secreted TGF-β1 regulated by multiple proteins. Among these regulators, latency-associated peptide and latent TGF-β-binding protein inhibit TGF-β1 function, whereas different proteases and integrins activate it. Progress in understanding the factors responsible for the bioactivity and expression of TGF-β1 has revealed that the dysregulation of TGF-β1 activation and expression is closely associated with the chronic respiratory inflammatory diseases involved in CRS. This review of the regulation of TGF-β1 activation and expression provides insight into the mechanism responsible for the different CRS subtypes, which will help further the investigation of novel therapy targets for the treatment of CRS.

Role of the Aryl Hydrocarbon Receptor in the Pathogenesis of Chronic Rhinosinusitis with Nasal Polyps

A predominant Th17 population is a marker of chronic rhinosinusitis with nasal polyps (CRSwNP) in Chinese patients. As a ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR) plays a vital role in promoting or inhibiting specific Th cell development. However, its role in CRSwNP remains to be defined. The aim of the present study was to investigate whether AhR, which regulates Th17 cell differentiation, played a role in the pathogenesis of CRSwNP by evaluating AhR expression in nasal polyps and peripheral blood mononuclear cells (PBMCs) obtained from CRSwNP patients. Forty-eight patients (atopic, 24; non-atopic, 24) and 13 controls were studied. To explore the role of AhR in CRSwNP, we analyzed the expression of AhR, retinoid-related orphan receptor C (RORC), interleukin (IL)-17, and IL-10 and the differentiation of Th17 using mRNA or protein detection methods. Notably, the expression of AhR was reduced in CRSwNP, and the expression of AhR was lower in the atopic group than in the non-atopic group. However, there was a very low level of Th17 and its associated factors (RORC, IL-17) in the control group compared to the two CRSwNP groups. In particular, the polarization of Th17 cells in atopic CRSwNP patients was increased compared with non-atopic individuals. In addition, ITE intervention in PBMCs promoted AhR expression and attenuated Th17 responses, demonstrating that AhR was more likely to suppress Th17 cells differentiation in Chinese CRSwNP patients. This information is valuable for obtaining a clear understanding of the pathogenesis of CRSwNP. Moreover, patients with atopic CRSwNP may exhibit reduced expression of AhR, leading to aggravation of the disproportionate distribution of Th17 cells in polyp tissues and PBMCs, thereby suggesting that atopic CRSwNP has a distinct pathogenesis from that of non-atopic CRSwNP.

Andrographolide suppresses IL-6/Stat3 signaling in peripheral blood mononuclear cells from patients with chronic rhinosinusitis with nasal polyps.

The mechanisms underlying the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) remain largely unknown. CRSwNP has garnered considerable public health concern owing to its high incidence and unsatisfactory treatment outcomes. Herbal remedies are promising candidates for the treatment of CRSwNP. We examined the utility of andrographolide, a diterpenoid lactone extracted from the Chinese herb Andrographis paniculata, an anti-inflammatory agent for CRSwNP treatment by evaluating interleukin (IL)-6 and IL-17 production and monitoring T helper 17 (Th17) differentiation of peripheral blood mononuclear cells (PBMCs) isolated from 20 Chinese CRSwNP patients and 11 control subjects. All CRSwNP patients exhibited clinical features of CRSwNP. Andrographolide significantly inhibited IL-6 and IL-17 production, suppressed p-Stat3 expression, and inhibited Th17 differentiation of PBMCs in vitro. These findings suggested that andrographolide has useful anti-inflammatory properties and could be used for the treatment of CRSwNP.

Transforming growth factor-β1 promotes Treg commitment in nasal polyposis after intranasal steroid treatment.

BackgroundA predominant Th17 population and impaired Treg function is the marker of nasal polyposis (NP) in Chinese patients. TGF-β1, a multifunction cytokine, is a vital factor involved in inducing or restricting specific Th cell development. However, its role in NP has still not been well understood.MethodsIn a double-blind trial, 30 subjects were randomized into 2 groups (15 steroid-treated NP, 15 untreated NP), and 15 normal subjects were allocated as control group. We analyzed the expression of TGF-β1, p-Smad2, p-STAT3, Smad7, SOCS3, IL-10, IL-17A, Foxp3, and RORc in the NP tissue of Chinese patients using mRNA and protein detection methods.ResultsTGF-β1, p-Smad2, IL-10, SOCS3, and Foxp3 expression was higher in steroid-treated NP patients than in untreated NP patients. Conversely, expression of p-STAT3, Smad7, IL-17A, and RORc was higher in untreated NP patients than in steroid-treated NP patients, demonstrating that TGF-β1 was more likely to contribute to Treg commitment in Chinese NP patients after intranasal steroid treatment.ConclusionsTGF-β1 may be a signature Treg cytokine, which is valuable for obtaining a clear understanding of the pathogenesis of NP. Moreover, intranasal steroid treatment attenuated the chronic inflammatory response in these patients by promoting Smad-dependent Treg functions and reducing STAT3-mediated Th17 reactions.

Hypoxia disrupts aryl hydrocarbon receptor signaling and the Th17 response in allergic rhinitis patients

HighlightsHypoxia to allergic rhinitis (AR) is an important and emerging field.Under hypoxic conditions, HIF‐1&agr; competes to combine ARNT and thus restrain the activation of AhR transcriptional response.Hypoxia associated with AR can promote Th17 differentiation and IL‐17 production but suppress the IL‐10 expression.Hypoxia is capable of reducing AhR activity, and HIF‐1&agr; is intimately involved in the pathogenesis of AR. Background: Hypoxic conditions area key feature of allergic rhinitis (AR), however, the role of hypoxia in AR remains to be fully understood. The aim of this study was to survey the effect of hypoxia on the Th17 response in AR patients by investigating the action of hypoxia‐influenced signaling pathways on Th17 differentiation. Methods: 23 AR patients and 15 healthy controls were recruited for this study. Under normoxia and hypoxic conditions, the expression of HIF‐1&agr;, AhR, CYP1A1 and CYP1B1 and the presence of Th17 cells in CD4+T cells were measured. Furthermore, the amount of ARNT combined with either HIF‐1&agr; or AhR was determined after the exposure of 2‐(1H‐Indol‐3‐ylcarbonyl)‐4‐thiazolecarboxylic acid methyl easter (ITE) with normoxia and hypoxia. Results: HIF‐1&agr; and AhR expression were higher in CD4+T cells from AR patients than in those from healthy controls. In a hypoxic environment, the expression of HIF‐1&agr; was elevated in CD4+T cells of both AR patients and healthy controls. Meanwhile, the suppressive effects of a non‐toxic AhR ligand (ITE) on the Th17 response and its positive effects on IL‐10 production were suppressed in the cells of AR patients and healthy controls under hypoxia. These effects were arisen from HIF‐1&agr; out‐competing AhR for ARNT binding which limited the activity of the AhR pathway. Conclusions: The present results suggest that hypoxia is capable of promoting the Th17 response by reducing AhR activity via HIF‐1&agr; activity. Thus hypoxia may be intimately involved in the pathogenesis of AR.