Bariaa Khalil, Narjes Saheb Sharif-Askari, Balachandar Selvakumar, Bushra Mdkhana, Ibrahim Hachim, Adel Zakri, Jennifer Hundt, Qutayba Hamid, Rabih Halwani
{"title":"Vitamin D3 suppresses NLRP3 inflammasome pathway and enhances steroid sensitivity in a neutrophilic steroid hyporesponsive asthma mouse model.","authors":"Bariaa Khalil, Narjes Saheb Sharif-Askari, Balachandar Selvakumar, Bushra Mdkhana, Ibrahim Hachim, Adel Zakri, Jennifer Hundt, Qutayba Hamid, Rabih Halwani","doi":"10.1007/s00011-025-02009-4","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>Severe steroid hyporesponsive asthma is a heterogeneous group of chronic inflammatory diseases characterized by irreversible airflow limitation, hyperresponsiveness, inflammation, and remodelling of the airways. Severe asthmatics account for more than 60% of asthma-related healthcare cost worldwide given they are hyporesponsive to corticosteroids and due to the absence of targeted treatment specifically for the T helper-17 (Th-17) high endotype. Hence, there is a clear unmet need to investigate other treatment options to control patients' symptoms. The role of the NLRP3 inflammasome pathway has been highlighted in the literature to contribute to disease pathogenesis and severity. Interestingly, vitamin D3 is an important regulator of the NLRP3 inflammasome pathway.</p><p><strong>Methods: </strong>Using house dust mite (HDM) and lipopolysaccharide (LPS), we induced a neutrophilic steroid hyporesponsive asthma mouse model to investigate the effect of vitamin D3 on downregulating the NLRP3 inflammasome pathway and enhancing steroid sensitivity.</p><p><strong>Results: </strong>We showed that calcitriol, the active form of vitamin D3, could downregulate the NLRP3 inflammasome pathway. This was associated with a significant reduction in airway hyperresponsiveness, IL-17 release, neutrophil infiltration, and mucus secretion. Further, calcitriol enhanced steroid sensitivity by inhibiting the expression of GR-β. Mechanistically, calcitriol targeted the NLRP3 inflammasome to ubiquitination.</p><p><strong>Conclusions: </strong>Our research highlights the potential use of calcitriol as a low cost and accessible supplement to ameliorate airway inflammation during severe steroid hyporesponsive asthma.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"74 1","pages":"51"},"PeriodicalIF":4.8000,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Inflammation Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00011-025-02009-4","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Objective: Severe steroid hyporesponsive asthma is a heterogeneous group of chronic inflammatory diseases characterized by irreversible airflow limitation, hyperresponsiveness, inflammation, and remodelling of the airways. Severe asthmatics account for more than 60% of asthma-related healthcare cost worldwide given they are hyporesponsive to corticosteroids and due to the absence of targeted treatment specifically for the T helper-17 (Th-17) high endotype. Hence, there is a clear unmet need to investigate other treatment options to control patients' symptoms. The role of the NLRP3 inflammasome pathway has been highlighted in the literature to contribute to disease pathogenesis and severity. Interestingly, vitamin D3 is an important regulator of the NLRP3 inflammasome pathway.
Methods: Using house dust mite (HDM) and lipopolysaccharide (LPS), we induced a neutrophilic steroid hyporesponsive asthma mouse model to investigate the effect of vitamin D3 on downregulating the NLRP3 inflammasome pathway and enhancing steroid sensitivity.
Results: We showed that calcitriol, the active form of vitamin D3, could downregulate the NLRP3 inflammasome pathway. This was associated with a significant reduction in airway hyperresponsiveness, IL-17 release, neutrophil infiltration, and mucus secretion. Further, calcitriol enhanced steroid sensitivity by inhibiting the expression of GR-β. Mechanistically, calcitriol targeted the NLRP3 inflammasome to ubiquitination.
Conclusions: Our research highlights the potential use of calcitriol as a low cost and accessible supplement to ameliorate airway inflammation during severe steroid hyporesponsive asthma.
期刊介绍:
Inflammation Research (IR) publishes peer-reviewed papers on all aspects of inflammation and related fields including histopathology, immunological mechanisms, gene expression, mediators, experimental models, clinical investigations and the effect of drugs. Related fields are broadly defined and include for instance, allergy and asthma, shock, pain, joint damage, skin disease as well as clinical trials of relevant drugs.