M2 Macrophages Upregulated by Allergen Exposure in Seasonal Allergic Rhinitis.

INTRODUCTION: Macrophages play a central role in balancing the immune response by switching phenotypes between the M1 and M2 profiles according to a delicate equilibrium. Based on a previous clinical trial (NCT03649139), this study aimed to evaluate the change in M2 macrophages during pollen exposure in seasonal allergic rhinitis (SAR). METHODS: Nasal symptom scores were recorded. Peripheral M2 macrophages were investigated according to cell surface markers, and M2-associated cytokine/chemokine release in serum and nasal secretion were assessed. In vitro pollen stimulation tests were performed, and polarized macrophage subsets were analyzed by flow cytometry. RESULTS: Compared to baseline, the percentage of peripheral CD163+ M2 macrophages in CD14+ monocytes increased during the pollen season (p < 0.001) and at the end of treatment (p = 0.004) in the SLIT group. The percentage of CD206+CD86- M2 cells in M2 macrophages during the pollen season was higher than that at baseline and at the end of SLIT. On the other hand, the percentage of CD206-CD86+ M2 cells in M2 macrophages significantly increased at the end of treatment in the SLIT group compared to baseline (p = 0.049), the peak pollen period (p = 0.017), and the placebo group (p = 0.0023). M2-associated chemokines CCL26 and YKL-40 were significantly increased during the pollen season in the SLIT group and remained higher at the end of SLIT than at baseline. Correspondingly, in vitro study demonstrated that Artemisia annua promoted M2 macrophage polarization in pollen-induced AR patients. CONCLUSION: Significant M2 macrophage polarization was promoted when patients with SAR were exposed to the allergen, either naturally exposed in pollen seasons or subjectively continuously exposed during the course of SLIT.

Investigation of the Value of T 2 Mapping in the Prediction of Eosinophilic Chronic Rhinosinusitis With Nasal Polyps.

OBJECTIVES: Patients with eosinophilic chronic rhinosinusitis with nasal polyps (eosCRSwNP) usually have more extensive sinus disease, severe symptoms, and poorer disease control compared with patients with non-eosCRSwNP. Separating these entities will be crucial for patient management. The purpose of this study is to investigate T 1, T 2 , and apparent diffusion coefficient (ADC) values of the nasal polyps in patients with CRSwNP and evaluate the usefulness of these parameters for differentiating these diseases. METHODS: Sinonasal magnetic resonance imaging was performed in 36 patients with eosCRSwNP and 20 patients with non-eosCRSwNP (including T 1 mapping, T 2 mapping, and diffusion-weighted imaging) before surgery. The T 1 , T 2 , and ADC values were calculated and correlated with pathologically assessed inflammatory cells of nasal polyps. RESULTS: Significant higher T 2 value, higher eosinophil count, and lower lymphocyte count of the nasal polyps were observed in eosCRSwNP than those in non-eosCRSwNP. There was no significant difference in T 1 or ADC values between the 2 groups. T 2 value was correlated with eosinophil count and lymphocyte count in CRSwNP. The area under the curve of T 2 value for predicting eosCRSwNP was 0.78 with 89.9% sensitivity and 60.0% specificity. CONCLUSION: T 2 value is a promising imaging biomarker for predicting eosCRSwNP. It can help to distinguish eosCRSwNP from non-eosCRSwNP.

Influence of postural changes on nasal resistance in patients with obstructive sleep apnea.

OBJECTIVE: Increased nasal resistance (NR) can augment upper airway collapse in patients with obstructive sleep apnea (OSA). Posture change can lead to altered nasal resistance. Our study aimed to investigate the influence of posture changes on NR in patients with OSA. METHODS: Healthy controls without subjective nasal obstruction (apnea-hypopnea index (AHI) < 5 events/h), patients with OSA and subjective nasal obstruction, and patients with OSA and no subjective nasal obstruction were recruited. NR was measured by active anterior rhinomanometry in sitting, supine, left-lateral, and right-lateral postural positions. Total NR and postural change-related NR increments were calculated and compared among groups. RESULTS: In total, 26 healthy controls and 72 patients with OSA (mean AHI 39.7 ± 24.8 events/h) were recruited. Of patients with OSA, 38/72 (53%) had subjective nasal obstruction. Compared with controls, patients with OSA and no subjective nasal obstruction had lower total NR (inspiration, p = 0.037; expiration, p = 0.020) in the supine postural position. There was no difference in sitting, left-lateral, and right-lateral total NR among groups. Total NR was higher in lateral compared to sitting posture in both patients with OSA and in controls. The NR increment for sitting to supine postural change was significantly lower in patients with OSA (inspiration, p = 0.003; expiration, p = 0.005) compared with controls. The change in NR showed no statistically significant difference among groups in supine-left or supine-right postural change. CONCLUSION: Patients with OSA had lower supine total NR and lower total NR increment in the sitting to supine postural change, which may be related to a different posture-related NR regulatory mechanism. This study provides a new exploratory direction for the compensatory mechanism of the upper airway to collapse during sleep.

Chinese Expert Consensus on the Use of Biologics in Patients with Chronic Rhinosinusitis (2022, Zhuhai).

BACKGROUND: Chronic rhinosinusitis (CRS) is a common inflammatory disease in otolaryngology, mainly manifested as nasal congestion, nasal discharge, facial pain/pressure, and smell disorder. CRS with nasal polyps (CRSwNP), an important phenotype of CRS, has a high recurrence rate even after receiving corticosteroids and/or functional endoscopic sinus surgery. In recent years, clinicians have focused on the application of biological agents in CRSwNP. However, it has not reached a consensus on the timing and selection of biologics for the treatment of CRS so far. SUMMARY: We reviewed the previous studies of biologics in CRS and summarized the indications, contraindications, efficacy assessment, prognosis, and adverse effects of biologics. Also, we evaluated the treatment response and adverse reactions of dupilumab, omalizumab, and mepolizumab in the management of CRS and made recommendations. KEY MESSAGES: Dupilumab, omalizumab, and mepolizumab have been approved for the treatment of CRSwNP by the US Food and Drug Administration. Type 2 and eosinophilic inflammation, need for systemic steroids or contraindication to systemic steroids, significantly impaired quality of life, anosmia, and comorbid asthma are required for the use of biologics. Based on current evidence, dupilumab has the prominent advantage in improving quality of life and reducing the risk of comorbid asthma in CRSwNP among the approved monoclonal antibodies. Most patients tolerate biological agents well in general with few major or severe adverse effects. Biologics have provided more options for severe uncontrolled CRSwNP patients or patients who refuse to have surgery. In the future, more novel biologics will be assessed in high-quality clinical trials and applied clinically.

Vitamin D Improves the Effect of Glucocorticoids on Attenuating Lipopolysaccharide-Induced IL-6 Production via TLR4/NF-κB Pathway in Human Respiratory Epithelial Cells.

BACKGROUND: Glucocorticoid (GC) resistance results in unsatisfactory outcomes in chronic rhinosinusitis with nasal polyps (CRSwNP) patients. Previous studies have shown that calcitriol, the active form of vitamin D, alone or in combination with corticosteroids, exerts crucial immunomodulatory effects on inflammatory responses. However, whether vitamin D can improve the effect of GCs to attenuate inflammation in the epithelium of CRSwNP remains unclear. METHODS: A human bronchial epithelial cell line (Beas-2B) and primary human nasal epithelial cells (HNECs) obtained from 10 patients with CRSwNP were exposed to lipopolysaccharide (LPS) for 24 h to establish an inflammation model. LPS-stimulated HNECs and Beas-2B cells were treated with/without dexamethasone in the presence or absence of calcitriol pretreatment for 24 h. The expression levels of interleukin-6 (IL-6) mRNA and protein were determined by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Toll-like receptor 4 (TLR4)/NF-κB pathway related markers were examined by western blotting. One-way ANOVA or the Kruskal-Wallis test with post hoc analysis were used for multiple comparisons among groups. RESULTS: The production of IL-6 in Beas-2B cells and primary HNECs after LPS stimulation was significantly increased, which could be inhibited by dexamethasone or calcitriol alone. However, significant inhibition of IL-6 production was observed in the calcitriol plus dexamethasone group. Further analysis showed that calcitriol could enhance the effect of dexamethasone in inhibiting LPS-induced overexpression of TLR4, Myd88, and phosphorylation of p65. CONCLUSION: Our findings demonstrated that vitamin D could improve the effect of GCs to alleviate the level of IL-6 induced by LPS via the TLR4/NF-κB pathway in human respiratory epithelial cells.

Antihistamine premedication improves safety and efficacy of allergen immunotherapy.

BACKGROUND: Allergen immunotherapy (AIT)-associated adverse events are a major concern for safety and efficacy of AIT. Presently, there is no consensus to whether antihistamine premedication could improve such conditions. OBJECTIVE: To identify the superiority of antihistamine pretreatment in AIT. METHODS: A comprehensive literature search for randomized controlled trials reporting the effects of antihistamine premedication on safety and efficacy of AIT was performed in MEDLINE, Embase, and Cochrane Library databases. Safety was evaluated according to the number of patients reporting systemic adverse reactions (SARs, the primary outcome) and efficacy according to the number of patients achieving target maintenance dose (TMD) and sustained unresponsiveness to allergen. RESULTS: A total of 11 randomized controlled trials (including 609 patients) satisfied the inclusion criteria for the meta-analysis. All premedication protocols were temporary. Pooled analysis revealed that compared with control patients, significantly fewer antihistamine-pretreated patients reported total and moderate-to-severe SARs (odds ratio [OR], 0.36; 95% confidence interval [CI], 0.23-0.56; P < .05 and OR, 0.20; 95% CI, 0.06-0.74; P < .05, respectively) and total and moderate-to-severe SAR episodes (OR, 0.42; 95% CI, 0.34-0.53; P < .05 and OR, 0.09; 95% CI, 0.01-0.50; P < .05, respectively). Similarly, antihistamine pretreatment significantly increased the number of patients achieving TMD (OR, 2.94; 95% CI, 1.72-5.03; P < .05), but not sustained unresponsiveness (OR, 1.65; 95% CI, 0.77-3.54; P = 0.2), compared with the control group. Subgroup analysis according to different allergens and dose-escalating approaches also displayed superiority of antihistamine pretreatment than control. CONCLUSION: Antihistamine premedication can markedly improve safety and efficacy of AIT by reducing frequency and severity of SAR and increasing TMD.

Artemisia annua-sublingual immunotherapy for seasonal allergic rhinitis: A randomized controlled trial.

BACKGROUND: Artemisia annua is an important autumnal pollen allergen for seasonal allergic rhinitis (SAR) in northern China. To date, no study has investigated allergen immunotherapy with A annua. We aimed to investigate the efficacy and mechanisms underlying A annua-sublingual immunotherapy (SLIT). METHODS: This was a randomized, double-blind, placebo-controlled phase III clinical trial involving 71 SAR patients, randomized to SLIT with A annua extract (n = 47) or placebo (n = 24) for 32 weeks. Total nasal symptom score (TNSS; primary clinical end point) was evaluated at baseline (peak pollen phase (PPP) in the previous year), initiation of A annua-SLIT, 1st PPP during SLIT, end of SLIT and 2nd PPP during follow-up. Blood samples and nasal secretions were collected at beginning and after SLIT for assessment of T cells and inflammatory mediators. Safety was assessed according to adverse events (AEs) reported. RESULTS: Artemisia annua-SLIT significantly reduced TNSS to a greater level from baseline (from 9.45 ± 1.68 to 6.16 ± 2.27) than placebo (from 9.29 ± 2.09 to 9.05 ± 2.40) at the 1st PPP (P < .001) and sustained the improvement in symptoms throughout to the 2nd PPP. Preseasonal A annua-SLIT for 16 weeks significantly decreased Th2 cells, increased nTreg and Tr1 cells in blood; and increased cystatin 1 (CST1) in nasal secretion after 16 and 32 weeks compared with pretreatment. Overall, 17/47 patients experienced mild local AEs and 2 patients mild systemic AEs, after A annua-SLIT. CONCLUSION: Artemisia annua-SLIT is an efficacious and safe treatment in patients with A annua SAR.

Epithelium-derived cystatin SN enhances eosinophil activation and infiltration through IL-5 in patients with chronic rhinosinusitis with nasal polyps.

BACKGROUND: The interaction between epithelial cells and immune cells plays an important role in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP); however, the mechanism or mechanisms underlying TH-biased inflammation in this process are largely unknown. Profiling protein expression in patients with CRSwNP by using shotgun proteomics suggested that cystatin SN (CST1), a type 2 cysteine protease inhibitor, might play a role because this was expressed with the greatest difference in patients with eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) and those with noneosinophilic chronic rhinosinusitis with nasal polyps (nonECRSwNP). OBJECTIVES: We sought to investigate the expression and role of CST1 in modulating eosinophilic inflammation in patients with CRSwNP. METHODS: Sinonasal tissues were collected from 192 patients with ECRSwNP, 52 patients with nonECRSwNP, and 40 control subjects. CST1 mRNA expression, localization, and concentration in the tissues were measured by using real-time PCR, in situ hybridization, immunohistochemistry, and an ELISA. Recombinant CST1 was used to further explore the function of the molecule in dispersed nasal polyp cells and eosinophils extracted from polyp tissues and peripheral blood. RESULTS: CST1 was mainly expressed by epithelial cells and significantly increased in patients with ECRSwNP but decreased in patients with nonECRSwNP compared with that in control subjects. CST1 expression was further increased in patients with ECRSwNP and comorbid asthma and correlated with eosinophil percentages in tissue samples. CST1 was induced by IL-4 and IL-13 in tissue from both patients with ECRSwNP and those with nonECRSwNP and repressed by IL-17A in patients with nonECRSwNP in the presence of neutrophils. CST1 enhanced eosinophil activation and recruitment through induction of IL-5. CONCLUSION: Epithelium-derived CST1 modulates eosinophil activation and recruitment, expression of which could be regulated by TH2 and TH17 cytokines.

Endotypes of chronic rhinitis: A cluster analysis study.

BACKGROUND: Chronic rhinitis (CR) is currently regarded as a syndrome, which presents as several endotypes. The aim of this study was to identify the CR endotype clusters and investigate the inflammatory patterns associated with the different endotypes. METHODS: A total of 259 CR patients and 20 control subjects were enrolled in this prospective study. Twelve clinical variables were analyzed using cluster analysis and five inflammatory variables were measured to investigate the inflammatory patterns associated with the different clusters. RESULTS: Six endotype clusters of CR were defined in the Chinese CR patients. Patients in cluster 1 (38.6%) were diagnosed as allergic rhinitis (AR) without asthma, and in cluster 2 (13.5%) as AR with asthma, with all demonstrating positive results for local eosinophils and high levels of local and serum IgE. Similarly, patients in cluster 3 (18.6%) were diagnosed as nonallergic rhinitis with eosinophilia syndrome (NARES) without asthma and in cluster 5 (5.0%) as NARES with asthma, with all demonstrating positive results for local eosinophils, and negative results for both local and serum IgE. Patients in cluster 4 (4.6%) were diagnosed as local allergic rhinitis and showed positive results for local eosinophils and local IgE, but negative results for serum IgE, whereas patients in cluster 6 (19.7%) were diagnosed as idiopathic rhinitis because of high symptoms scores, but negative findings for local eosinophils, local IgE, and serum IgE. CONCLUSIONS: Chinese CR patients may be clustered into six endotypes with different inflammatory patterns, which may help in delivering individualized treatment.

Expression of IL-22 in the Skin Causes Th2-Biased Immunity, Epidermal Barrier Dysfunction, and Pruritus via Stimulating Epithelial Th2 Cytokines and the GRP Pathway.

Increased expression of Th22 cytokine IL-22 is a characteristic finding in atopic dermatitis (AD). However, the specific role of IL-22 in the pathogenesis of AD in vivo has yet to be elucidated. Consistent with observations in human AD, IL-22 was significantly increased in the AD skin of mice after epicutaneous sensitization to house dust mite allergen. Utilizing a skin-specific inducible transgenic system, we show in the present study that expression of IL-22 in the skin of mice caused an AD-like phenotype characterized by chronic pruritic dermatitis associated with Th2-biased local and systemic immune responses, downregulation of epidermal differentiation complex genes, and enhanced dermatitis upon epicutaneous allergen exposure. IL-22 potently induced the expression of gastrin-releasing peptide (GRP), a neuropeptide pruritogen, in dermal immune cells and sensory afferents and in their skin-innervating sensory neurons. IL-22 also differentially upregulated the expression of GRP receptor (GRPR) on keratinocytes of AD skin. The number of GRP+ cells in the skin correlated with the AD severity and the intensity of pruritus. IL-22 directly upregulated the expression of epithelial-derived type 2 cytokines (thymic stromal lymphopoietin and IL-33) and GRP in primary keratinocytes. Furthermore, GRP not only strongly induced thymic stromal lymphopoietin but it also increased the expression of IL-33 and GRPR synergistically with IL-22. Importantly, we found that the expression of GRP was strikingly increased in the skin of patients with AD. These results indicate that IL-22 plays important pathogenic roles in the initiation and development of AD, in part through inducing keratinocyte production of type 2 cytokines and activation of the GRP/GRPR pathway.

Recent developments and highlights in allergen immunotherapy.

Allergen immunotherapy (AIT) is the only disease-modifying treatment option for patients with IgE-mediated inhalant allergies. Though used in clinical practice for more than 100 years, most innovations in AIT efficacy and safety have been developed in the last two decades. This expert review aimed to highlight the recent progress in AIT for both application routes, the sublingual (SLIT) and subcutaneous (SCIT) forms. As such, it covers recent aspects regarding efficacy and safety in clinical trials and real-life data and outlines new concepts in consensus and position papers as well as in guidelines for AIT. Potential clinical and nonclinical biomarkers are discussed. This review also focuses on potential future perspectives in AIT, such as alternative application routes, immune-modulating adjuvants, and recombinant vaccines. In conclusion, this state of the art review provides a comprehensive overview of AIT and highlights unmet needs for the future.

Chronic rhinosinusitis in Asia.

Chronic rhinosinusitis (CRS), although possibly overdiagnosed, is associated with a high burden of disease and is often difficult to treat in those truly affected. Recent research has demonstrated that inflammatory signatures of CRS vary around the world, with less eosinophilic and more neutrophilic inflammation found in Asia compared with Europe and North America. Although in the Western world about 80% of nasal polyps carry a type 2 signature, this might be between 20% and 60% in China and Korea or Thailand, respectively. These differences are associated with a lower asthma comorbidity and risk of disease recurrence after surgery in the Asian population. As a hallmark of severe type 2 inflammation, eosinophils attacking Staphylococcus aureus at the epithelial barrier have been described recently; they also can be found in a subgroup of Asian patients with nasal polyps. Furthermore, the percentage of type 2 signature disease in patients with CRS is dramatically increasing ("eosinophilic shift") in several Asian countries over the last 20 years. Establishing an accurate diagnosis along with considering the current and shifting patterns of inflammation seen in Asia will enable more effective selection of appropriate pharmacotherapy, surgical therapy, and eventually biotherapy. Determining the causes and pathophysiology for this eosinophilic shift will require additional research.

Diversity of TH cytokine profiles in patients with chronic rhinosinusitis: A multicenter study in Europe, Asia, and Oceania.

BACKGROUND: To date, no study has evaluated the diversity of TH cell cytokine patterns of patients with chronic rhinosinusitis (CRS) among centers in different continents using identical methods. OBJECTIVE: We sought to assess TH cytokine profiles in patients with CRS from Europe, Asia, and Australia. METHODS: Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP; n = 435) and control subjects (n = 138) were recruited from centers in Adelaide, Benelux, Berlin, Beijing, Chengdu, and Tochigi. Nasal mucosal concentrations of TH2, TH17, and TH1 cytokines; eosinophilic cationic protein (ECP); myeloperoxidase (MPO); IL-8; and tissue total and Staphylococcus aureus enterotoxin (SE)-specific IgE were measured by using identical tools. RESULTS: Combinations of TH1/TH2/TH17 cytokine profiles in patients with CRSwNP varied considerably between regions. CRSwNP tissues from patients from Benelux, Berlin, Adelaide, and Tochigi were TH2 biased, whereas those from Beijing mainly demonstrated TH2/TH1/TH17 mixed patterns, and patients from Chengdu showed an even lower TH2 expression. Concentrations of IL-8 and tissue total IgE in patients with CRSwNP were significantly higher than those in control subjects in all regions. More than 50% of patients with CRSwNP in Benelux, Berlin, Adelaide, and Tochigi showed a predominantly eosinophilic endotype compared with less than 30% of patients in Beijing and Chengdu. SE-specific IgE was found in significantly greater numbers in patients with CRSwNP from Benelux, Adelaide, and Tochigi and significantly lower numbers in patients from Beijing and Chengdu. Moreover, the TH1/TH2/TH17 cytokine profiles in patients with CRSsNP showed diversity among the 6 regions. CONCLUSION: TH cytokine levels, eosinophilic/neutrophilic patterns, and SE-specific IgE expressions show extreme diversity among patients with CRS from Europe, Asia, and Oceania.

Cellular phenotyping of chronic rhinosinusitis with nasal polyps.

BACKGROUND: Defining the phenotypes of chronic rhinosinusitis with nasal polyps (CRSwNP) with prognosis may lead to delivery of personalized treatment. This study aimed to identify cellular phenotypes of CRSwNP using cluster analysis and define an algorithm for different clusters associated with polyp recurrence. METHODS: Overall, 366 patients with CRSwNP were enrolled in this retrospective analysis. Eighteen variables, including clinical characteristics and tissue/peripheral inflammatory cells assessments, were selected for factor analysis. Unsupervised cluster analysis was performed after variables reduction and standardization and differences in polyp recurrence during follow-up for a minimum of 24 months were analysed among clusters. Discriminant analysis was further used to develop a clinically useful algorithm for predicting clustering. RESULTS: Five phenotypic clusters were identified. Clusters 1 and 2 were plasma cell-dominant and lymphocyte-dominant phenotypes, respectively. Cluster 3 revealed a mixed inflammatory pattern. Cluster 4 was characterized by infiltration of predominantly neutrophils. Cluster 5 was characterized by a marked tissue eosinophilia and highest recurrence rate of 98.5%. The clinical algorithm predicted clustering with 93.7% accuracy. CONCLUSIONS: Chinese CRSwNP patients may be classified into five phenotypes with different polyp recurrence rates, based on the presence of predominantly plasma cells, lymphocytes, neutrophils, eosinophils or mixed inflammatory cells in polyps.

Effect of budesonide transnasal nebulization in patients with eosinophilic chronic rhinosinusitis with nasal polyps.

BACKGROUND: There is little evidence on the efficacy of glucocorticoid transnasal nebulization therapy in patients with eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP). OBJECTIVE: We sought to evaluate the immunologic and remodeling effects of budesonide transnasal nebulization in patients with eosinophilic CRSwNP. METHODS: Sixty patients with eosinophilic CRSwNP were randomized to receive budesonide or placebo treatment for 14 days by means of transnasal nebulization in a double-blind manner. Endoscopic polyp size scores (maximum = 6 points, Kennedy score) and visual analog scale scores for nasal symptoms were assessed before and after treatment. Similarly, polyp samples were evaluated for inflammatory cytokines, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) by using an immunoassay; collagen by using histochemistry; eosinophils by using hematoxylin and eosin stain; and T-cell subsets by using flow cytometry. RESULTS: Budesonide transnasal nebulization significantly reduced polyp size compared with placebo (mean difference between groups, -0.73 units; 95% CI, -1.15 to -0.32 units; P = .002) and improved symptoms. Polyp IL-5 and eotaxin expression decreased significantly, whereas TGF-ß and IL-10 expression increased. Expression of IFN-γ and IL-17 was not altered. Budesonide transnasal nebulization consistently reduced eosinophil infiltration and TH2 cell frequency and increased natural regulatory T-cell and type 1 regulatory T-cell frequencies. Indices of remodeling, including albumin, MMP-2, MMP-7, MMP-8, and MMP-9, were significantly decreased, whereas collagen deposition and TIMP-1, TIMP-2, and TIMP-4 levels were significantly increased. Budesonide transnasal nebulization did not suppress the hypothalamic-pituitary-adrenal axis or cause any serious side effects. CONCLUSION: Short-term budesonide transnasal nebulization is an effective and safe treatment option in patients with eosinophilic CRSwNP, achieving clinical improvement by regulating remodeling, cytokine expression, and T-cell subset distribution.

TRPA1-dependent pruritus in IL-13-induced chronic atopic dermatitis.

Chronic debilitating pruritus is a cardinal feature of atopic dermatitis (AD). Little is known about the underlying mechanisms. Antihistamines lack efficacy in treating itch in AD, suggesting the existence of histamine-independent itch pathways in AD. Transient receptor potential ankyrin 1 (TRPA1) is essential in the signaling pathways that promote histamine-independent itch. In this study, we tested the hypothesis that TRPA1-dependent neural pathways play a key role in chronic itch in AD using an IL-13-transgenic mouse model of AD. In these mice, IL-13 causes chronic AD characterized by intensive chronic itch associated with markedly enhanced growth of dermal neuropeptide-secreting afferent nerve fibers and enhanced expression of TRPA1 in dermal sensory nerve fibers, their dorsal root ganglia, and mast cells. Inhibition of TRPA1 with a specific antagonist in these mice selectively attenuated itch-evoked scratching. Genetic deletion of mast cells in these mice led to significantly diminished itch-scratching behaviors and reduced TRPA1 expression in dermal neuropeptide containing afferents in the AD skin. Interestingly, IL-13 strongly stimulates TRPA1 expression, which is functional in calcium mobilization in mast cells. In accordance with these observations in the AD mice, TRPA1 expression was highly enhanced in the dermal afferent nerves, mast cells, and the epidermis in the lesional skin biopsies from patients with AD, but not in the skin from healthy subjects. These studies demonstrate a novel neural mechanism underlying chronic itch in AD and highlight the complex interactions among TRPA1(+) dermal afferent nerves and TRPA1(+) mast cells in a Th2-dominated inflammatory environment.