Childhood asthma clusters reveal neutrophil‐predominant phenotype with distinct gene expression

Su, Ming-Wei; Lin, Wen Chang; Tsai, Chien‐Hsiung; Chiang, Bor‐Luen; Yang, Yao‐Hsu; Lin, Yu-Tsan; Wang, Li‐Chieh; Lee, J.‐H.; Chou, Chin Cheng; Wu, Yi‐Fan; Yeh, Y.‐L.; Lee, Y. L.

doi:10.1111/all.13439

Cited by 45 publications

(45 citation statements)

References 42 publications

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“…Pathophysiology behind subgroups of non‐type 2 asthma remains poorly understood. Patients with neutrophilic and mixed asthma respond poorly to corticosteroid therapy, and increased numbers of neutrophils with persistent eosinophilia are seen in severe asthma and sudden‐onset fatal asthma . In both types of complex phenotypes, other factors such as genetics, epithelial barrier dysfunction, innate immune response, environmental exposures, viral infections, and comorbidities may further modulate inflammation, bringing the stability of dominant physiopathological mechanisms to question .…”

Section: Introductionmentioning

confidence: 99%

Tight junction, mucin, and inflammasome‐related molecules are differentially expressed in eosinophilic, mixed, and neutrophilic experimental asthma in mice

Tan

Hagner

Ruchti

et al. 2018

Allergy

142

131

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Background: Asthma is a chronic respiratory disease with marked clinical and pathophysiological heterogeneity. Specific pathways are thought to be involved in the pathomechanisms of different inflammatory phenotypes of asthma; however, direct in vivo comparison has not been performed. Methods:We developed mouse models representing three different phenotypes of allergic airway inflammation-eosinophilic, mixed, and neutrophilic asthma via different methods of house dust mite sensitization and challenge. Transcriptomic analysis of the lungs, followed by the RT-PCR, western blot, and confocal microscopy, was performed. Primary human bronchial epithelial cells cultured in air-liquid interface were used to study the mechanisms revealed in the in vivo models.Results: By whole-genome transcriptome profiling of the lung, we found that airway tight junction (TJ), mucin, and inflammasome-related genes are differentially expressed in these distinct phenotypes. Further analysis of proteins from these families revealed that Zo-1 and Cldn18 were downregulated in all phenotypes, while increased Cldn4 expression was characteristic for neutrophilic airway inflammation.Mucins Clca1 (Gob5) and Muc5ac were upregulated in eosinophilic and even more in neutrophilic phenotype. Increased expression of inflammasome-related molecules such as Nlrp3, Nlrc4, Casp-1, and IL-1β was characteristic for neutrophilic asthma. In addition, we showed that inflammasome/Th17/neutrophilic axis cytokine-IL-1βmay transiently impair epithelial barrier function, while IL-1β and IL-17 increase mucin expressions in primary human bronchial epithelial cells.Conclusion: Our findings suggest that differential expression of TJ, mucin, and inflammasome-related molecules in distinct inflammatory phenotypes of asthma may be linked to pathophysiology and might reflect the differences observed in the clinic. K E Y W O R D Sendotype, epithelial barrier, house dust mite, phenotype, precision medicine Tan and Hagner equal first-author contribution.

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Section: Introductionmentioning

confidence: 99%

Tight junction, mucin, and inflammasome‐related molecules are differentially expressed in eosinophilic, mixed, and neutrophilic experimental asthma in mice

Tan

Hagner

Ruchti

et al. 2018

Allergy

142

131

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“…Asthma is believed to be a most common respiratory disorder threatening hundreds of millions individuals worldwide, and the prevalence has increased considerably over the past decades. Inflammation of the airway is a key characteristic of asthma, the release of mediators from the inflammatory cells including eosinophils, lymphocytes, mast cells, and neutrophils (Amin, 2016;Januskevicius et al, 2016;Su et al, 2018), as well as inflammatory cytokines, such as interferon (IFN)-g, interleukin (IL)-1b, IL-6, and tumor necrosis factor (TNF)-a (Yokoyama et al, 1995;Wei-xu et al, 2014;Huang et al, 2016;Diao et al, 2017), has been proposed to contribute directly or indirectly to changes in airway structure and function.…”

Section: Introductionmentioning

confidence: 99%

Icariin Protects Hippocampal Neurons From Endoplasmic Reticulum Stress and NF-κB Mediated Apoptosis in Fetal Rat Hippocampal Neurons and Asthma Rats

Liu

Sun

et al. 2020

Front. Pharmacol.

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Icariin is a main component of the Chinese medicinal plant Epimedium brevicornu Maxim, exhibits potent activity against inflammatory diseases. Our previous data demonstrated the valid bioactivity of icariin on mitigating rodent asthma. Endoplasmic reticulum (ER) stress and nuclear factor-kB (NF-kB) pathway were involved in the pathogenesis of asthma. However, it remains poorly defined that whether icariin could inhibit ER stress and NF-kB mediated apoptosis in asthma and further influence the central neural system. Herein, we investigated the effects of icariin on primary cultured fetal rat hippocampal neurons and OVA LPS-OVA induced asthma rat model. Asthma rat models were established by ovalbumin (OVA) and lipopolysaccharide (LPS) intraperitoneal injection and OVA inhalational challenge. Airway resistance was analyzed to evaluate lung function after last challenge and pathological changes were detected on lung tissues. Assessment of inflammatory cells counts in bronchoalveolar lavage fluids (BALF) were performed and ELISA was used to determine levels of interleukin (IL)-1b, tumor necrosis factor-a, IL-6, and interferon-g in serum. Protein expression of BiP and IRE-1a, XBP-1s and phosphorylation-IkBa (p-IkBa), IkBa, and p65 as well as cytochrome c, caspase-3 (cleaved caspase-3), and caspase-9 (cleaved caspase-9) were tested by Western blot. We found that icariin could remarkably improve pulmonary function and reduce inflammatory cells in the lung, levels of inflammatory cytokines, and ER stress related proteins as well as NF-kB were prominently suppressed by icariin. Our results suggested that icariin had an inhibitory effect on airway inflammation and neuroprotective effect on ER stress and NF-kB mediated apoptosis in asthma rats and cultured fetal rat hippocampal neurons, which may provide new mechanistic insights into the asthma prevention and treatment of icariin.

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“…3,4 Allergic asthma is the most common asthma phenotype with an earlier onset. [5][6][7] Nonallergic or intrinsic asthma includes a subset of patients with asthma without allergic sensitization. 8,9 These patients show quite variable response to standard therapy.…”

Section: Introductionmentioning

confidence: 99%

“…12 It is expressed at a low level on unstimulated blood eosinophils and upregulated by interleukin (IL)-5. 7 Chemoattractant receptor homolog expressed on Th2 cells (CRTH2) represents one of two functional prostaglandin D2 (PGD2) receptors. CRTH2 is expressed on various types of cells; eosinophils, Th2 cells, ILC2, basophils, CD8 + T cells, mast cells, macrophages, monocytes, and dendritic cells.…”

Section: Introductionmentioning

confidence: 99%

Impact of high‐altitude therapy on type‐2 immune responses in asthma patients

Boonpiyathad

Capova

Duchna

et al. 2019

Allergy

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Background: Asthma patients present with distinct immunological profiles, with a predominance of type 2 endotype. The aim of this study was to investigate the impact of high-altitude treatment on the clinical and immunological response in asthma. Methods: Twenty-six hospitalized asthma patients (nine eosinophilic allergic; EA, nine noneosinophilic allergic; NEA and eight noneosinophilic nonallergic; NN) and nine healthy controls in high altitude for 21 days were enrolled in the study. We assessed eosinophils, T cells, Tregs, and innate lymphoid cells (ILC) from peripheral blood using flow cytometry. Results: The number of eosinophils (both resting and activated) and chemoattractant receptor homolog expressed on Th2 cells (CRTH2)-expressing CD4 + and CD8 + T cells decreased significantly in EA patients after altitude treatment. The frequency of CRTH2 + Tregs as decreased significantly in all the asthma phenotypes as well as the frequency of ILC2 was significantly reduced in EA after altitude treatment. After 21 days of altitude therapy, CRTH2-expressing ILC2, CD4 + and CD8 + T cells and Treg cells showed attenuated responses to exogenous PGD2. Furthermore, PGD2 signaling via CRTH2 was found to diminish the suppressive function of CRTH2 + Tregs which partially normalized during high-altitude treatment. Improved asthma control was particularly evident in allergic asthma patients and correlated with decreased frequencies of CRTH2 + Treg cells in EA patients. Serum IL-5 and IL-13 decreased during climate treatment in asthma patients with high baseline levels. Conclusions: Asthma treatment in high altitude reduced the type 2 immune response, corrected the increased CRTH2 expression and its dysregulated functions. | 85 BOONPIYATHAD eT Al.

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Childhood asthma clusters reveal neutrophil‐predominant phenotype with distinct gene expression

Cited by 45 publications

References 42 publications

Tight junction, mucin, and inflammasome‐related molecules are differentially expressed in eosinophilic, mixed, and neutrophilic experimental asthma in mice

Tight junction, mucin, and inflammasome‐related molecules are differentially expressed in eosinophilic, mixed, and neutrophilic experimental asthma in mice

Icariin Protects Hippocampal Neurons From Endoplasmic Reticulum Stress and NF-κB Mediated Apoptosis in Fetal Rat Hippocampal Neurons and Asthma Rats

Impact of high‐altitude therapy on type‐2 immune responses in asthma patients

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