Smoking shifts human small airway epithelium club cells toward a lesser differentiated population

Rostami, Mahboubeh; LeBlanc, Michelle G.; Strulovici-Barel, Yael; Zuo, Wu-Lin; Mezey, Jason G.; O’Beirne, Sarah L.; Kaner, Robert J.; Leopold, Philip L.; Crystal, Ronald G.

doi:10.1038/s41525-021-00237-1

Cited by 14 publications

(8 citation statements)

References 71 publications

(64 reference statements)

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“…The finding that secretory cells are the predominant source of pIgR expression is consistent with published human and murine scRNA-seq datasets 27 33–37 and with the known role of secretory cells in immune defense and airway homeostasis 35 . Although ciliated cells also produce low levels of pIgR and are more numerous than secretory cells in distal airways, we did not observe lung pathology in mice with ciliated cell-specific deletion of pIgR.…”

Section: Discussionsupporting

confidence: 87%

Secretory cells are the primary source of pIgR in small airways

Blackburn

Schaff

Gutor

et al. 2021

Preprint

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BackgroundLoss of secretory immunoglobulin A (SIgA) is common in COPD small airways and likely contributes to disease progression. We hypothesized loss of SIgA results from reduced expression of pIgR, a chaperone protein needed for SIgA transcytosis, in the COPD small airway epithelium.MethodspIgR-expressing cells were defined and quantified at single-cell resolution in human airways using RNA in-situ hybridization, immunostaining, and single-cell RNA sequencing. Complementary studies in mice utilized immunostaining, primary murine tracheal epithelial cell (MTEC) culture, and transgenic mice with secretory or ciliated cell-specific knockout of pIgR. SIgA degradation by human neutrophil elastase or secreted bacterial proteases from non-typeable Haemophilus influenzae (NTHi) was evaluated in vitro.ResultsWe found that secretory cells are the predominant cell type responsible for pIgR expression in human and murine airways. Loss of SIgA in small airways was not associated with a reduction in secretory cells but rather a reduction in pIgR protein expression despite intact PIGR mRNA expression. Neutrophil elastase and NTHi-secreted proteases are both capable of degrading SIgA in vitro and may also contribute to a deficient SIgA immunobarrier in COPD.InterpretationLoss of the SIgA immunobarrier in small airways of patients severe COPD is complex and likely results from both pIgR-dependent defects in IgA transcytosis and SIgA degradation.Key MessagesWhat is the key question? Localized SIgA deficiency in small airways is an established driver of COPD pathogenesis, but the mechanism of loss remains unclear. We hypothesized loss of SIgA is due to reduced numbers of pIgR-expressing cells in SIgA-deficient small airways.What is the bottom line? pIgR is primarily expressed by secretory cells in human and murine airways. Although numbers of secretory cells are similar between SIgA-deficient and SIgA-replete airways in COPD, there is reduced expression of pIgR protein, but not mRNA, in SIgA-deficient airways. Additionally, host and bacterial proteases degrade SIgA in vitro, suggesting loss of SIgA may relate to both impaired transcytosis and increased degradation.Why read on? This study highlights the complexity of SIgA immunobarrier maintenance and suggests that strategies aimed at restoring the SIgA immunobarrier will need to account for both impaired transcytosis and degradation by host and/or bacterial proteases.

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Section: Discussionsupporting

confidence: 87%

Secretory cells are the primary source of pIgR in small airways

Blackburn

Schaff

Gutor

et al. 2021

Preprint

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“…CC16 protein is the primary product secreted by Club cells which are present throughout the respiratory epithelium [11]. Club cells play a key role in host defense through the expression of genes involved in immune, anti-protease, anti-bacterial, and physical barrier function [22]. Cigarette smoke exposure directly damages the club cells reducing their abundance, differentiation, biological defense functions, and increases number of mucous-producing cells [3,8,11,22].…”

Section: Discussionmentioning

confidence: 99%

“…Club cells play a key role in host defense through the expression of genes involved in immune, anti-protease, anti-bacterial, and physical barrier function [22]. Cigarette smoke exposure directly damages the club cells reducing their abundance, differentiation, biological defense functions, and increases number of mucous-producing cells [3,8,11,22]. As such, smokeinduced injury to club cells and subsequent decreased CC16 may contribute to an increased susceptibility to COPD [12].…”

Section: Discussionmentioning

confidence: 99%

Relationships of serum CC16 levels with smoking status and lung function in COPD

et al. 2022

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Background:The club cell secretory protein (CC16) has anti-inflammatory and antioxidant effects, and low CC16 serum levels have been associated with both risk and progression of COPD, yet the interaction between smoking and CC16 on lung function outcomes remains unknown. Methods:Utilizing cross-sectional data on United States veterans, CC16 serum concentrations were measured by ELISA and log transformed for analyses. Spirometry was conducted and COPD status was defined by post-bronchodilator FEV 1 /FVC ratio < 0.7. Smoking measures were self-reported on questionnaire. Multivariable logistic and linear regression were employed to examine associations between CC16 levels and COPD, and lung function with adjustment for covariates. Unadjusted Pearson correlations described relationships between CC16 level and lung function measures, pack-years smoked, and years since smoking cessation. Results:The study population (N = 351) was mostly male, white, with an average age over 60 years. An interaction between CC16 and smoking status on FEV 1 /FVC ratio was demonstrated among subjects with COPD (N = 245, p = 0.01). There was a positive correlation among former smokers and negative correlation among current or never smokers with COPD. Among former smokers with COPD, CC16 levels were also positively correlated with years since smoking cessation, and inversely related with pack-years smoked. Increasing CC16 levels were associated with lower odds of COPD (OR adj = 0.36, 95% CI 0.22-0.57, P adj < 0.0001).Conclusions: Smoking status is an important effect modifier of CC16 relationships with lung function. Increasing serum CC16 corresponded to increases in FEV 1 /FVC ratio in former smokers with COPD versus opposite relationships in current or never smokers. Additional longitudinal studies may be warranted to assess relationship of CC16 with smoking cessation on lung function among subjects with COPD.

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“…The apoptosis score was calculated using the genes in the apoptosis pathway (hsa04210). The club host defense score was calculated using SCGB1A1 , CXCL17 , CXCL1 , CXCL6 , C3 , CD55 , B2M , PIGR , TLR5 , LCN2 , LYZ , BPIFB1 , GSTP1 , RDH10 , AKR1C1 , DHRS9 , CYP2F1 , MGST1 , CYP4B1 , SERPINA1 , SLPI , WFDC2 , SERPINB3 , CST3 , CTNNB1 , CXADR , CLDN1 , CLDN4 , OCLN , TFF3 , MUC1 , MUC5B , ITGAV , and ITGB1 [ 28 ]. The mucus secretion score was calculated using genes in the GO term mucus secretion (GO: 0,070,254).…”

Section: Methodsmentioning

confidence: 99%

Cellular metabolic basis of altered immunity in the lungs of patients with COVID-19

Zhao

et al. 2022

Med Microbiol Immunol

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Metabolic pathways drive cellular behavior. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes lung tissue damage directly by targeting cells or indirectly by producing inflammatory cytokines. However, whether functional alterations are related to metabolic changes in lung cells after SARS-CoV-2 infection remains unknown. Here, we analyzed the lung single-nucleus RNA-sequencing (snRNA-seq) data of several deceased COVID-19 patients and focused on changes in transcripts associated with cellular metabolism. We observed upregulated glycolysis and oxidative phosphorylation in alveolar type 2 progenitor cells, which may block alveolar epithelial differentiation and surfactant secretion. Elevated inositol phosphate metabolism in airway progenitor cells may promote neutrophil infiltration and damage the lung barrier. Further, multiple metabolic alterations in the airway goblet cells are associated with impaired muco-ciliary clearance. Increased glycolysis, oxidative phosphorylation, and inositol phosphate metabolism not only enhance macrophage activation but also contribute to SARS-CoV-2 induced lung injury. The cytotoxicity of natural killer cells and CD8 + T cells may be enhanced by glycerolipid and inositol phosphate metabolism. Glycolytic activation in fibroblasts is related to myofibroblast differentiation and fibrogenesis. Glycolysis, oxidative phosphorylation, and glutathione metabolism may also boost the aging, apoptosis and proliferation of vascular smooth muscle cells, resulting in pulmonary arterial hypertension. In conclusion, this preliminary study revealed a possible cellular metabolic basis for the altered innate immunity, adaptive immunity, and niche cell function in the lung after SARS-CoV-2 infection. Therefore, patients with COVID-19 may benefit from therapeutic strategies targeting cellular metabolism in future. Supplementary Information The online version contains supplementary material available at 10.1007/s00430-021-00727-0.

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Smoking shifts human small airway epithelium club cells toward a lesser differentiated population

Cited by 14 publications

References 71 publications

Secretory cells are the primary source of pIgR in small airways

Secretory cells are the primary source of pIgR in small airways

Relationships of serum CC16 levels with smoking status and lung function in COPD

Cellular metabolic basis of altered immunity in the lungs of patients with COVID-19

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