Pub Date : 2026-03-01Epub Date: 2025-12-13DOI: 10.1016/j.jaci.2025.11.014
Kritika Khanna PhD , Monica Tang MD , Nathan D. Jackson PhD , Mats W. Johansson PhD , Eugene R. Bleecker MD , Mario Castro MD, MPH , Suzy A. Comhair PhD , Loren C. Denlinger MD, PhD , Serpil C. Erzurum MD , Annette T. Hastie PhD , Wendy Moore MD , Elliot Israel MD , Bruce D. Levy MD , Nizar N. Jarjour MD , David T. Mauger PhD , Brenda R. Phillips MS , Kaharu Sumino MD, MPH , Sally E. Wenzel MD , Prescott G. Woodruff MD, MPH , Max A. Seibold PhD , John V. Fahy MD, MSc
Background
Inhibition of thymic stromal lymphopoietin (TSLP) improves asthma control, but the relationships between airway TSLP levels and clinical and immunologic features of asthma are unclear.
Objective
We sought to determine associations between airway TSLP, disease control, and airway remodeling in asthma.
Methods
We measured TSLP protein in sputum from patients with mild-to-moderate asthma (University of California San Francisco cohort, n = 137), patients with moderate-to-severe asthma (Severe Asthma Research Program-3 cohort, n = 397), and healthy controls (n = 95). We explored how sputum TSLP levels relate to measures of lung function and exacerbations, airway inflammation, and lung image–based measures of mucus plugging and airway remodeling.
Results
The upper 95th percentile value for sputum TSLP concentration in healthy controls was 1.6 pg/mL; 16% of the University of California San Francisco cohort and 33.5% of the Severe Asthma Research Program-3 cohort had TSLP concentrations above this value. High sputum TSLP levels occurred most often in patients with severe asthma showing clinical traits typical of type 2 inflammation. There was considerable overlap between subgroups with high levels of TSLP and eosinophilic inflammation. High sputum TSLP levels were associated with a strong sputum cell gene expression profile for type 2 immune responses and a weak expression for type 1 responses. High sputum TSLP levels were also associated with high sputum MUC5AC expression and high scores for mucus plugging, air trapping, and other measures of airway remodeling on computed tomography lung scans.
Conclusion
High levels of airway TSLP in asthma are associated with more severe asthma with predominantly type 2 airway immune responses and with mucus plugging, air trapping, and airway remodeling.
{"title":"High airway thymic stromal lymphopoietin in asthma is associated with type 2 inflammation, mucus plugging, and airway remodeling","authors":"Kritika Khanna PhD , Monica Tang MD , Nathan D. Jackson PhD , Mats W. Johansson PhD , Eugene R. Bleecker MD , Mario Castro MD, MPH , Suzy A. Comhair PhD , Loren C. Denlinger MD, PhD , Serpil C. Erzurum MD , Annette T. Hastie PhD , Wendy Moore MD , Elliot Israel MD , Bruce D. Levy MD , Nizar N. Jarjour MD , David T. Mauger PhD , Brenda R. Phillips MS , Kaharu Sumino MD, MPH , Sally E. Wenzel MD , Prescott G. Woodruff MD, MPH , Max A. Seibold PhD , John V. Fahy MD, MSc","doi":"10.1016/j.jaci.2025.11.014","DOIUrl":"10.1016/j.jaci.2025.11.014","url":null,"abstract":"<div><h3>Background</h3><div>Inhibition of thymic stromal lymphopoietin (TSLP) improves asthma control, but the relationships between airway TSLP levels and clinical and immunologic features of asthma are unclear.</div></div><div><h3>Objective</h3><div>We sought to determine associations between airway TSLP, disease control, and airway remodeling in asthma.</div></div><div><h3>Methods</h3><div>We measured TSLP protein in sputum from patients with mild-to-moderate asthma (University of California San Francisco cohort, n = 137), patients with moderate-to-severe asthma (Severe Asthma Research Program-3 cohort, n = 397), and healthy controls (n = 95). We explored how sputum TSLP levels relate to measures of lung function and exacerbations, airway inflammation, and lung image–based measures of mucus plugging and airway remodeling.</div></div><div><h3>Results</h3><div>The upper 95th percentile value for sputum TSLP concentration in healthy controls was 1.6 pg/mL; 16% of the University of California San Francisco cohort and 33.5% of the Severe Asthma Research Program-3 cohort had TSLP concentrations above this value. High sputum TSLP levels occurred most often in patients with severe asthma showing clinical traits typical of type 2 inflammation. There was considerable overlap between subgroups with high levels of TSLP and eosinophilic inflammation. High sputum TSLP levels were associated with a strong sputum cell gene expression profile for type 2 immune responses and a weak expression for type 1 responses. High sputum TSLP levels were also associated with high sputum <em>MUC5AC</em> expression and high scores for mucus plugging, air trapping, and other measures of airway remodeling on computed tomography lung scans.</div></div><div><h3>Conclusion</h3><div>High levels of airway TSLP in asthma are associated with more severe asthma with predominantly type 2 airway immune responses and with mucus plugging, air trapping, and airway remodeling.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"157 3","pages":"Pages 616-626"},"PeriodicalIF":11.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145760091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-12-23DOI: 10.1016/j.jaci.2025.12.994
Su Yu MD, PhD , Yao Xu MD, PhD , Yizhen Li MD , Xiaoyu Pan MD , Zixin Zhao BS , Chaoying Gu MD, PhD , Huibin Yin MD, PhD , Qianwen Shan BS , Yuemeng Wu MD, PhD , Yu Wang MD, PhD , Hao Wu MD, PhD , Yehua Cai MD, MS , Xu Yao MD, PhD , Yan-Gang Sun PhD , Wei Li MD, PhD
Background
Atopic dermatitis (AD) is a chronic inflammatory skin disorder with severe itching, posing a great burden on both the physical and mental health of patients. AD is frequently complicated by sympathetic nervous system (SNS) dysfunction.
Objective
We sought to explore the interplay between skin inflammation and SNS activity during AD development.
Methods
Using clinical cohort data and murine models, we used impression mold technique, simultaneous noninvasive recording of electrocardiogram and skin sympathetic nerve activity, ultrasound, immunohistochemistry, and RNA sequencing to investigate the impact of AD inflammation on sympathetic function and structure. Conversely, chemogenetic manipulations were used to assess the effects of the SNS on AD-related inflammation and itch.
Results
We revealed significant SNS dysfunction in patients with AD, which was manifested by diminished perspiration and attenuated electrical responses, and ultrasound data showed compensatory hypertrophy in the sympathetic ganglia. These impairments were partially reversed in patients with AD treated with dupilumab. Moreover, MC903-induced AD-like dermatitis exhibited histologic and molecular indications of inflammatory stress and injury in the sympathetic ganglia. Chemogenetic inhibition of Phox2b+ sympathetic neurons exacerbated MC903-induced cutaneous inflammation and itch sensation in mice, whereas targeted activation of sympathetic neurons attenuated both clinical and histologic manifestations of AD-like dermatitis.
Conclusions
Our data revealed a detrimental cycle between AD skin inflammation and sympathetic nerve dysfunction.
{"title":"Sympathetic nerve dysfunction exacerbates skin inflammation in atopic dermatitis","authors":"Su Yu MD, PhD , Yao Xu MD, PhD , Yizhen Li MD , Xiaoyu Pan MD , Zixin Zhao BS , Chaoying Gu MD, PhD , Huibin Yin MD, PhD , Qianwen Shan BS , Yuemeng Wu MD, PhD , Yu Wang MD, PhD , Hao Wu MD, PhD , Yehua Cai MD, MS , Xu Yao MD, PhD , Yan-Gang Sun PhD , Wei Li MD, PhD","doi":"10.1016/j.jaci.2025.12.994","DOIUrl":"10.1016/j.jaci.2025.12.994","url":null,"abstract":"<div><h3>Background</h3><div>Atopic dermatitis (AD) is a chronic inflammatory skin disorder with severe itching, posing a great burden on both the physical and mental health of patients. AD is frequently complicated by sympathetic nervous system (SNS) dysfunction.</div></div><div><h3>Objective</h3><div>We sought to explore the interplay between skin inflammation and SNS activity during AD development.</div></div><div><h3>Methods</h3><div>Using clinical cohort data and murine models, we used impression mold technique, simultaneous noninvasive recording of electrocardiogram and skin sympathetic nerve activity, ultrasound, immunohistochemistry, and RNA sequencing to investigate the impact of AD inflammation on sympathetic function and structure. Conversely, chemogenetic manipulations were used to assess the effects of the SNS on AD-related inflammation and itch.</div></div><div><h3>Results</h3><div>We revealed significant SNS dysfunction in patients with AD, which was manifested by diminished perspiration and attenuated electrical responses, and ultrasound data showed compensatory hypertrophy in the sympathetic ganglia. These impairments were partially reversed in patients with AD treated with dupilumab. Moreover, MC903-induced AD-like dermatitis exhibited histologic and molecular indications of inflammatory stress and injury in the sympathetic ganglia. Chemogenetic inhibition of <em>Phox2b</em><sup><em>+</em></sup> sympathetic neurons exacerbated MC903-induced cutaneous inflammation and itch sensation in mice, whereas targeted activation of sympathetic neurons attenuated both clinical and histologic manifestations of AD-like dermatitis.</div></div><div><h3>Conclusions</h3><div>Our data revealed a detrimental cycle between AD skin inflammation and sympathetic nerve dysfunction.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"157 3","pages":"Pages 677-692"},"PeriodicalIF":11.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145822998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-11-11DOI: 10.1016/j.jaci.2025.08.034
Diamant Thaçi MD , Vivian Laquer MD , Charles Lynde MD , Adam Reich MD, PhD , Weily Soong MD , Margitta Worm MD , Petra Arlert PhD , Allan Blemings MSc , Thomas Litman PhD , Britta C. Martel PhD , Martin Olesen MD, PhD , Ole E. Sørensen MD, PhD , Melinda Gooderham MD
Background
Atopic dermatitis (AD) is a chronic inflammatory skin disease in which increased IL-22 expression contributes to epidermal hyperplasia and barrier defects. Temtokibart is a monoclonal antibody targeting IL-22RA1 (IL-22 receptor subunit alpha-1), blocking the signaling of IL-22 and potentially also of IL-20 and IL-24.
Objective
We evaluated the efficacy and safety of temtokibart in adults with moderate-to-severe AD.
Methods
In this phase 2a study (NCT04922021), 58 adults were randomized 1:1 to subcutaneous temtokibart 450 mg or placebo every 2 weeks for 16 weeks, with an additional dose (450 mg) at week 1, followed by additional 16 weeks of safety follow-up. The primary end point was change in Eczema Area Severity Index (EASI) from baseline to week 16. Biomarkers in serum, including IL-22, were analyzed as an exploratory end point.
Results
Mean change in EASI from baseline to week 16 was significantly greater for temtokibart compared to placebo (−15.3 vs −3.5; P = .003), corresponding to 65.4% and 19.7% improvement for temtokibart and placebo groups, respectively. At week 16, greater proportions of patients receiving temtokibart relative to placebo obtained EASI-75 (41.6% vs 13.7%; P = .011), EASI-90 (30.8% vs 3.5%; P = .003), and EASI-100 (20.9% vs 0%; P = .006). Treatment with temtokibart was well tolerated, and no safety signals were observed. Further, temtokibart treatment was associated with a general reduction of systemic inflammatory proteins.
Conclusions
This proof-of-concept study demonstrates that targeting the IL-22 pathway with temtokibart is clinically effective with a favorable safety profile.
背景：过敏性皮炎（AD）是一种慢性炎症性皮肤病，IL-22表达增加导致表皮增生和屏障缺陷。Temtokibart是一种靶向IL-22RA1 （IL-22受体亚基α -1）的单克隆抗体，可阻断IL-22的信号传导，也可能阻断IL-20和IL-24的信号传导。目的评价替托基巴特治疗成人中重度AD的疗效和安全性。在这项2a期研究（NCT04922021）中，58名成年人以1:1的比例随机分配，每2周接受temtokibart皮下治疗450 mg或安慰剂，持续16周，在第1周增加剂量（450 mg），随后进行额外的16周安全随访。主要终点是湿疹区域严重指数（EASI）从基线到第16周的变化。分析血清中的生物标志物，包括IL-22，作为探索性终点。结果：与安慰剂组相比，替托基巴特组从基线到第16周的EASI平均变化显著大于安慰剂组（- 15.3 vs - 3.5; P = 0.003），对应于替托基巴特组和安慰剂组分别改善65.4%和19.7%。在第16周，接受temtokibart治疗的患者获得EASI-75 （41.6% vs 13.7%, P = 0.011）、EASI-90 （30.8% vs 3.5%, P = 0.003）和EASI-100 （20.9% vs 0%, P = 0.006）的比例高于安慰剂。替托基巴特治疗耐受性良好，未观察到安全信号。此外，替托基巴特治疗与全身炎症蛋白的普遍减少有关。结论：这项概念验证研究表明，temtokibart靶向IL-22通路是临床有效的，并且具有良好的安全性。
{"title":"Targeting IL-22RA1 with temtokibart: A novel approach in atopic dermatitis: Phase 2a monotherapy study results","authors":"Diamant Thaçi MD , Vivian Laquer MD , Charles Lynde MD , Adam Reich MD, PhD , Weily Soong MD , Margitta Worm MD , Petra Arlert PhD , Allan Blemings MSc , Thomas Litman PhD , Britta C. Martel PhD , Martin Olesen MD, PhD , Ole E. Sørensen MD, PhD , Melinda Gooderham MD","doi":"10.1016/j.jaci.2025.08.034","DOIUrl":"10.1016/j.jaci.2025.08.034","url":null,"abstract":"<div><h3>Background</h3><div>Atopic dermatitis (AD) is a chronic inflammatory skin disease in which increased IL-22 expression contributes to epidermal hyperplasia and barrier defects. Temtokibart is a monoclonal antibody targeting IL-22RA1 (IL-22 receptor subunit alpha-1), blocking the signaling of IL-22 and potentially also of IL-20 and IL-24.</div></div><div><h3>Objective</h3><div>We evaluated the efficacy and safety of temtokibart in adults with moderate-to-severe AD.</div></div><div><h3>Methods</h3><div>In this phase 2a study (NCT04922021), 58 adults were randomized 1:1 to subcutaneous temtokibart 450 mg or placebo every 2 weeks for 16 weeks, with an additional dose (450 mg) at week 1, followed by additional 16 weeks of safety follow-up. The primary end point was change in Eczema Area Severity Index (EASI) from baseline to week 16. Biomarkers in serum, including IL-22, were analyzed as an exploratory end point.</div></div><div><h3>Results</h3><div>Mean change in EASI from baseline to week 16 was significantly greater for temtokibart compared to placebo (−15.3 vs −3.5; <em>P</em> = .003), corresponding to 65.4% and 19.7% improvement for temtokibart and placebo groups, respectively. At week 16, greater proportions of patients receiving temtokibart relative to placebo obtained EASI-75 (41.6% vs 13.7%; <em>P</em> = .011), EASI-90 (30.8% vs 3.5%; <em>P</em> = .003), and EASI-100 (20.9% vs 0%; <em>P</em> = .006). Treatment with temtokibart was well tolerated, and no safety signals were observed. Further, temtokibart treatment was associated with a general reduction of systemic inflammatory proteins.</div></div><div><h3>Conclusions</h3><div>This proof-of-concept study demonstrates that targeting the IL-22 pathway with temtokibart is clinically effective with a favorable safety profile.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"157 3","pages":"Pages 666-676"},"PeriodicalIF":11.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145498676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-12-06DOI: 10.1016/j.jaci.2025.10.035
Elisabetta Granato PhD , Ida Cerqua PhD , Antonietta Rossi PhD , Maria Antonietta Riemma PhD , Maria Chiara Monti PhD , Giusy Ferraro PhD , Barbara Romano PhD , Maria Francesca Nanì PhD , Danilo D’Avino PhD , Martina Simonelli PhD , Joshua Malo MD , Francesca Polverino MD, PhD , Bruno D’Agostino MD , Giuseppe Cirino PhD , Fiorentina Roviezzo PhD
Background
Genetic polymorphisms in sphingolipid metabolism, particularly involving the orosomucoid-like 3 (ORMDL3) gene, have been associated with asthma risk. Notably, asthma prevalence and severity exhibit pronounced sex differences, emerging in childhood and persisting into adulthood. However, the molecular mechanisms underlying this sexual dimorphism remain incompletely elucidated.
Objective
We investigated whether ORMDL3 contributes to sex differences in airway function and asthma-like features.
Methods
ORMDL3 expression was measured in lung tissues from healthy male and female human donors and in human bronchial epithelial cells (BEAS-2B) after exposure to 17β-estradiol (E2), Dermatophagoides pteronyssinus 1 (Der p 1), or both. A murine preparation of asthma was used to evaluate sex-dependent differences in ORMDL3 expression, airway responsiveness, and remodeling. Pharmacologic modulation of estrogen signaling and the ORMDL3–sphingosine-1-phosphate (S1P) axis were used. Methods included quantitative real-time PCR, immunostaining, liquid chromatography–tandem mass spectrometry, and airway function measurements.
Results
Female lungs exhibited higher ORMDL3 expression than male lungs, and this correlated with elevated forced expiratory volume to forced vital capacity ratios in the same patients. In BEAS-2B cells, E2 significantly upregulated ORMDL3 and altered sphingolipid metabolism by inducing expression of ceramidase, sphingosine kinases 1/2, and S1P receptors. Der p 1 also increased ORMDL3 and triggered epithelial activation via inflammasome signaling, while E2 enhanced IFN-β signaling and MUC5AC expression. Combination Der p 1/E2 synergistically activated sphingolipid, interferon, and inflammasome pathways. These in vitro findings prompted in vivo investigation using a murine asthma preparation, where female mice displayed elevated ORMDL3, sphingosine, and S1P levels, with increased airway hyperresponsiveness and remodeling. Treatment with tamoxifen or E2 normalized airway hyperresponsiveness and S1P signaling across sexes. Allergen sensitization intensified female-biased ORMDL3 expression and airway inflammation. Inhibition of the ORMDL3-S1P axis attenuated asthma-like features only in female animals.
Conclusion
This study identifies ORMDL3 as an estrogen-responsive regulator of airway responsiveness that may contribute to sex-related differences in asthma features through modulation of sphingolipid metabolism.
鞘脂代谢的遗传多态性，尤其是orosomucid -样3 （ORMDL3）基因，与哮喘风险相关。值得注意的是，哮喘患病率和严重程度表现出明显的性别差异，从童年开始，一直持续到成年。然而，这种两性二态现象的分子机制仍未完全阐明。目的探讨ORMDL3是否与气道功能和哮喘样特征的性别差异有关。方法检测sormdl3在暴露于17β-雌二醇（E2）、翼龙皮肤ophaophaides pteronyssinus 1 （Der p 1）或两者后的健康男性和女性供者肺组织和人支气管上皮细胞（BEAS-2B）中的表达。用小鼠哮喘制剂来评估ORMDL3表达、气道反应性和重塑的性别依赖性差异。使用雌激素信号和ormdl3 -鞘氨醇-1-磷酸（S1P）轴的药理学调节。方法包括实时定量PCR、免疫染色、液相色谱-串联质谱法和气道功能测定。结果女性肺部的ORMDL3表达高于男性肺部，这与同一患者的用力呼气量与用力肺活量之比升高有关。在BEAS-2B细胞中，E2通过诱导神经酰胺酶、鞘磷脂激酶1/2和S1P受体的表达，显著上调ORMDL3并改变鞘脂代谢。Der p 1也增加ORMDL3并通过炎性体信号触发上皮活化，而E2增强IFN-β信号和MUC5AC表达。联合Der p 1/E2协同激活鞘脂、干扰素和炎性体途径。这些体外研究结果促进了小鼠哮喘制剂的体内研究，其中雌性小鼠表现出ORMDL3，鞘氨醇和S1P水平升高，气道高反应性和重塑增加。他莫昔芬或E2治疗可使两性气道高反应性和S1P信号正常化。过敏原致敏强化了女性偏倚的ORMDL3表达和气道炎症。ORMDL3-S1P轴的抑制仅在雌性动物中减弱了哮喘样特征。结论本研究确定ORMDL3是气道反应性的雌激素响应性调节剂，可能通过调节鞘脂代谢导致哮喘特征的性别相关差异。
{"title":"Sex hormones influence ORMDL3 expression: Implications for sex-associated asthma phenotype","authors":"Elisabetta Granato PhD , Ida Cerqua PhD , Antonietta Rossi PhD , Maria Antonietta Riemma PhD , Maria Chiara Monti PhD , Giusy Ferraro PhD , Barbara Romano PhD , Maria Francesca Nanì PhD , Danilo D’Avino PhD , Martina Simonelli PhD , Joshua Malo MD , Francesca Polverino MD, PhD , Bruno D’Agostino MD , Giuseppe Cirino PhD , Fiorentina Roviezzo PhD","doi":"10.1016/j.jaci.2025.10.035","DOIUrl":"10.1016/j.jaci.2025.10.035","url":null,"abstract":"<div><h3>Background</h3><div>Genetic polymorphisms in sphingolipid metabolism, particularly involving the orosomucoid-like 3 <em>(ORMDL3)</em> gene, have been associated with asthma risk. Notably, asthma prevalence and severity exhibit pronounced sex differences, emerging in childhood and persisting into adulthood. However, the molecular mechanisms underlying this sexual dimorphism remain incompletely elucidated.</div></div><div><h3>Objective</h3><div>We investigated whether <em>ORMDL3</em> contributes to sex differences in airway function and asthma-like features.</div></div><div><h3>Methods</h3><div><em>ORMDL3</em> expression was measured in lung tissues from healthy male and female human donors and in human bronchial epithelial cells (BEAS-2B) after exposure to 17β-estradiol (E2), <em>Dermatophagoides pteronyssinus</em> 1 (Der p 1), or both. A murine preparation of asthma was used to evaluate sex-dependent differences in <em>ORMDL3</em> expression, airway responsiveness, and remodeling. Pharmacologic modulation of estrogen signaling and the ORMDL3–sphingosine-1-phosphate (S1P) axis were used. Methods included quantitative real-time PCR, immunostaining, liquid chromatography–tandem mass spectrometry, and airway function measurements.</div></div><div><h3>Results</h3><div>Female lungs exhibited higher <em>ORMDL3</em> expression than male lungs, and this correlated with elevated forced expiratory volume to forced vital capacity ratios in the same patients. In BEAS-2B cells, E2 significantly upregulated ORMDL3 and altered sphingolipid metabolism by inducing expression of ceramidase, sphingosine kinases 1/2, and S1P receptors. Der p 1 also increased ORMDL3 and triggered epithelial activation via inflammasome signaling, while E2 enhanced IFN-β signaling and <em>MUC5AC</em> expression. Combination Der p 1/E2 synergistically activated sphingolipid, interferon, and inflammasome pathways. These <em>in vitro</em> findings prompted <em>in vivo</em> investigation using a murine asthma preparation, where female mice displayed elevated ORMDL3, sphingosine, and S1P levels, with increased airway hyperresponsiveness and remodeling. Treatment with tamoxifen or E2 normalized airway hyperresponsiveness and S1P signaling across sexes. Allergen sensitization intensified female-biased <em>ORMDL3</em> expression and airway inflammation. Inhibition of the ORMDL3-S1P axis attenuated asthma-like features only in female animals.</div></div><div><h3>Conclusion</h3><div>This study identifies ORMDL3 as an estrogen-responsive regulator of airway responsiveness that may contribute to sex-related differences in asthma features through modulation of sphingolipid metabolism.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"157 3","pages":"Pages 602-615.e7"},"PeriodicalIF":11.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145689940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-01-22DOI: 10.1016/j.jaci.2026.01.005
Edsel M. Abud MD, PhD , Seema S. Aceves MD, PhD
{"title":"Running out of air: Loss of hypoxia-inducible factor and CD73-dependent repair in eosinophilic esophagitis","authors":"Edsel M. Abud MD, PhD , Seema S. Aceves MD, PhD","doi":"10.1016/j.jaci.2026.01.005","DOIUrl":"10.1016/j.jaci.2026.01.005","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"157 3","pages":"Pages 599-601"},"PeriodicalIF":11.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146033212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-02-28DOI: 10.1016/S0091-6749(26)00047-3
{"title":"CME Calendar-AAAAI","authors":"","doi":"10.1016/S0091-6749(26)00047-3","DOIUrl":"10.1016/S0091-6749(26)00047-3","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"157 3","pages":"Pages A29-A30"},"PeriodicalIF":11.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147334785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-11-21DOI: 10.1016/j.jaci.2025.11.004
Pengda Fang MD , Mengzhen Wu MD , Junhai Chen MD , Wenlong Li MD , Yurong Bai MD, PhD , Wenyi Chen BS , Yue Li MD, PhD , Xinyue Wang MD, PhD , Zhenhao Xiao MD , Tong Wu BS , Qintai Yang MD, PhD , Yana Zhang MD, PhD
Background
Eosinophilic inflammation represents a hallmark pathologic feature of chronic rhinosinusitis with nasal polyps (CRSwNP). Although ceramides, the central sphingolipid metabolites, are implicated in asthma pathogenesis, their mechanistic contributions to CRSwNP remain poorly elucidated.
Objective
We sought to investigate the functions and associated mechanisms of ceramide in the pathogenesis of CRSwNP.
Methods
Immunofluorescence and absolute quantitative lipidomics analysis were performed to evaluate the levels of ceramide and its species in nasal biopsy samples. In vitro culture and stimulation of purified eosinophils from human peripheral blood to validate the function of ceramides. Small interfering RNA transfection and inhibition assays to determine the molecular mechanism.
Results
The expression levels of ceramide and its binding protein were enriched in eosinophilic CRSwNP. Increased Cer(18:1_24:1) was related with eosinophil extracellular trap (EET) counts and disease severity in patients with eosinophilic CRSwNP. Cer(18:1_24:1) potently induced eosinophils activation by promoting EET formation and release. Mechanistically, Cer(18:1_24:1)-induced elevated levels of reactive oxygen species (ROS)/mitochondrial ROS (mROS) promoted EET formation by upregulating PAD4/CitH3 on one hand, and drove the oligomerization of the N terminal of gasdermin D (GSDMD-N) and membrane pore formation to facilitate the EET release on the other hand. Furthermore, ceramide-binding protein PP2AC inhibition blocked EET formation and release by reduction of ROS/mROS production. Interestingly, selenium supplementation mitigated Cer(18:1_24:1)-induced EET production and release by decreasing production of ROS/mROS.
Conclusions
Aberrant ceramide accumulation fuels eosinophilic inflammation by promoting EET formation and release through the PP2AC-ROS/mROS-GSDMD-N pathway, which may contribute to the severity and progression of eosinophilic CRSwNP. These mechanistic insights may provide novel therapeutic strategies for eosinophil-driven inflammatory disorders.
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Pub Date : 2026-03-01Epub Date: 2026-02-28DOI: 10.1016/S0091-6749(26)00045-X
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