IFN-stimulated Gene Expression, Type 2 Inflammation, and Endoplasmic Reticulum Stress in Asthma

Bhakta, Nirav R.; Christenson, Stephanie A.; Nerella, Srilaxmi; Solberg, Owen D.; Nguyen, Christine; Choy, David F.; Jung, Kyle L.; Garudadri, Suresh; Bonser, Luke R.; Pollack, Joshua L.; Zlock, Lorna; Erle, David J.; Langelier, Charles; DeRisi, Joseph L.; Arron, Joseph R.; Fahy, John V.; Woodruff, Prescott G.

doi:10.1164/rccm.201706-1070oc

Cited by 93 publications

(102 citation statements)

References 53 publications

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“…The literature also suggests that the UPR via the IRE1/XBP1 axis or via ATF6α affects the epithelial cell responses to allergens or IL-13 stimulation, respectively (62). Similarly, ATF6α is known to regulate allergen-induced macrophage and airway smooth muscle responses (63-65).…”

Section: Figure 5bmentioning

confidence: 99%

“…Because of its complex nature, HDM likely activates several pattern recognition receptors and elicits a mixed inflammatory response, mucus metaplasia, and AHR (4). We have demonstrated that HDM challenge induces ER stress in the lung, thereby activating the unfolded protein response (UPR), which is associated with many hallmarks of allergic airway disease in humans and rodents (5)(6)(7)(8). The UPR is an adaptive response consisting of the activation of transducers protein kinase R-like ER kinase (PERK), Conjugated bile acids (CBAs), such as tauroursodeoxycholic acid (TUDCA), are known to resolve the inflammatory and unfolded protein response (UPR) in inflammatory diseases, such as asthma.…”

Section: Introductionmentioning

confidence: 99%

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Conjugated bile acids attenuate allergen-induced airway inflammation and hyperresposiveness by inhibiting UPR transducers

Nakada¹,

Bhakta²,

Korwin-Mihavics³

et al. 2019

JCI Insight

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Section: Figure 5bmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Conjugated bile acids attenuate allergen-induced airway inflammation and hyperresposiveness by inhibiting UPR transducers

Nakada¹,

Bhakta²,

Korwin-Mihavics³

et al. 2019

JCI Insight

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“…Transcriptomic analysis of bronchial brushings and biopsies indicates that considerable bronchial epithelial signalling heterogeneity exists in asthma and severe asthma . A major challenge ahead is the development of clinically applicable biomarkers that reflect these varied alterations of epithelial function.…”

Section: Discussionmentioning

confidence: 99%

“…39 Transcriptomic analysis of bronchial brushings and biopsies indicates that considerable bronchial epithelial signalling heterogeneity exists in asthma and severe asthma. 11,13,33,40 A major challenge ahead is the development of clinically applicable biomarkers that reflect these varied alterations of epithelial function. One example of such a biomarker is serum periostin, which has shown some potential in treatment selection/response for IL-4/13 targeted biological therapies in severe asthma.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of sputum columnar epithelial cells and products in distinct asthma phenotypes

Qin

Gibson

Simpson

et al. 2019

Clin Experimental Allergy

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Background Dysfunction of the bronchial epithelium plays an important role in asthma; however, its measurement is challenging. Columnar epithelial cells are often quantified, yet rarely analysed, in induced sputum studies. Objective We aimed to test whether sputum columnar epithelial cell proportion and count are altered in asthma, and whether they are associated with clinical and inflammatory variables. We aimed to test whether sputum‐based measures could provide a relatively non‐invasive means through which to monitor airway epithelial activation status. Methods We examined the relationship of sputum columnar epithelial cells with clinical and inflammatory variables of asthma in a large retrospective cross‐sectional cohort (901 participants with asthma and 138 healthy controls). In further studies, we used flow cytometry, microarray, qPCR and ELISA to characterize sputum columnar epithelial cells and their products. Results Multivariate analysis and generation of 90th centile cut‐offs (≥11% or ≥18.1 × 104/mL) to identify columnar epithelial cell “high” asthma revealed a significant relationship between elevated sputum columnar cells and male gender, severe asthma and non‐neutrophilic airway inflammation. Flow cytometry showed viable columnar epithelial cells were present in all sputum samples tested. An epithelial gene signature (SCGB3A1, LDLRAD1, FOXJ1, DNALI1, CFAP157, CFAP53) was detected in columnar epithelial cell‐high sputum. CLCA1 mRNA and periostin protein, previously identified biomarkers of IL‐13‐mediated epithelial activation, were elevated in columnar epithelial cell‐high sputum samples, but only when accompanied by eosinophilia. Conclusions & clinical relevance Sputum columnar epithelial cells are related to important clinical and inflammatory variables in asthma. Measurement of epithelial biomarkers in sputum samples could allow non‐invasive assessment of altered bronchial epithelium status in asthma.

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“…Co‐existence of T2‐high and T2‐low pathways has also been reported. Thus, RNA‐sequencing of airway epithelial brushings from asthmatic and healthy control subjects identified increased expression of T2 markers with IFN‐stimulated genes (ISGs), and endoplasmic reticulum (ER) stress‐related genes . ISGs inversely correlated with T2 markers and defined patients with reduced FEV 1 .…”

Section: Non‐t2 Pathwaysmentioning

confidence: 99%

Precision medicine for the discovery of treatable mechanisms in severe asthma

Chung

Adcock

2019

Allergy

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Although the complex disease of asthma has been defined as being heterogeneous, the extent of its endophenotypes remains unclear. The pharmacological approach to initiating treatment has, until recently, been based on disease control and severity.The introduction of antibody therapies targeting the Type 2 inflammation pathway for patients with severe asthma has resulted in the recognition of an allergic and an eosinophilic phenotype, which are not mutually exclusive. Concomitantly, molecular phenotyping based on a transcriptomic analysis of bronchial epithelial and sputum cells has identified a Type 2 high inflammation cluster characterized by eosinophilia and recurrent exacerbations, as well as Type 2 low clusters linked with IL-6 trans-signalling, interferon pathways, inflammasome activation and mitochondrial oxidative phosphorylation pathways. Systems biology approaches are establishing the links between these pathways or mechanisms, and clinical and physiologic features.Validation of these pathways contributes to defining endotypes and treatable mechanisms. Precision medicine approaches are necessary to link treatable mechanisms with treatable traits and biomarkers derived from clinical, physiologic and inflammatory features of clinical phenotypes. The deep molecular phenotyping of airway samples along with noninvasive biomarkers linked to bioinformatic and machine learning techniques will enable the rapid detection of molecular mechanisms that transgresses beyond the concept of treatable traits. K E Y W O R D Seosinophilic asthma, precision medicine, severe asthma, systems biology

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IFN-stimulated Gene Expression, Type 2 Inflammation, and Endoplasmic Reticulum Stress in Asthma

Abstract: ISG activation is prominent in asthma, independent of viral transcripts, orthogonal to type 2 inflammation, and associated with distinct clinical features. ER stress is associated with both type 2 inflammation and ISG expression.

Cited by 93 publications

References 53 publications

Conjugated bile acids attenuate allergen-induced airway inflammation and hyperresposiveness by inhibiting UPR transducers

Conjugated bile acids attenuate allergen-induced airway inflammation and hyperresposiveness by inhibiting UPR transducers

Dysregulation of sputum columnar epithelial cells and products in distinct asthma phenotypes

Precision medicine for the discovery of treatable mechanisms in severe asthma

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