Dysregulated lung stroma drives emphysema exacerbation by potentiating resident lymphocytes to suppress an epithelial stem cell reservoir

Wang, Chaoqun; Hyams, Ben; Allen, Nancy C.; Cautivo, Kelly M.; Monahan, Kiara; Zhou, Minqi; Dahlgren, Madelene W; Lizama, Carlos O; Matthay, Michael A.; Wolters, Paul J.; Molofsky, Ari B.; Peng, Tien

doi:10.1016/j.immuni.2023.01.032

Cited by 32 publications

(22 citation statements)

References 48 publications

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“…136 Additionally, in a viral model of COPD exacerbation, it was shown that IFNγ derived from tissue-resident lymphocytes including T RM cells suppressed alveolar stem cell growth, promoting emphysema exacerbation. 137 Together, these data suggest a potential role of T RM cells, particularly CD8 + T RM cells, in the development or exacerbation of COPD. Since there are currently no effective therapeutics for COPD, targeting the pathological functions of CD8 + T RM cells may pave the way for the development of potent treatment strategies against COPD in the future.…”

Section: T Rm In Copd and Ipfmentioning

confidence: 83%

“…Moreover, CD69‐deficient mice exhibited reduced inflammation after smoking 136 . Additionally, in a viral model of COPD exacerbation, it was shown that IFN‐γ derived from tissue‐resident lymphocytes including T RM cells suppressed alveolar stem cell growth, promoting emphysema exacerbation 137 . Together, these data suggest a potential role of T RM cells, particularly CD8 + T RM cells, in the development or exacerbation of COPD.…”

Section: Trm and Chronic Respiratory Diseasementioning

confidence: 91%

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Tissue‐resident memory T cells and lung immunopathology

Cheon

Son

Sun

2023

Immunological Reviews

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Summary Rapid reaction to microbes invading mucosal tissues is key to protect the host against disease. Respiratory tissue‐resident memory T (TRM) cells provide superior immunity against pathogen infection and/or re‐infection, due to their presence at the site of pathogen entry. However, there has been emerging evidence that exuberant TRM‐cell responses contribute to the development of various chronic respiratory conditions including pulmonary sequelae post‐acute viral infections. In this review, we have described the characteristics of respiratory TRM cells and processes underlying their development and maintenance. We have reviewed TRM‐cell protective functions against various respiratory pathogens as well as their pathological activities in chronic lung conditions including post‐viral pulmonary sequelae. Furthermore, we have discussed potential mechanisms regulating the pathological activity of TRM cells and proposed therapeutic strategies to alleviate TRM‐cell‐mediated lung immunopathology. We hope that this review provides insights toward the development of future vaccines or interventions that can harness the superior protective abilities of TRM cells, while minimizing the potential for immunopathology, a particularly important topic in the era of coronavirus disease 2019 (COVID‐19) pandemic.

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Section: T Rm In Copd and Ipfmentioning

confidence: 83%

Section: Trm and Chronic Respiratory Diseasementioning

confidence: 91%

Tissue‐resident memory T cells and lung immunopathology

Cheon

Son

Sun

2023

Immunological Reviews

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“…Our analysis further unveiled two potential IFN-γ-mediated mechanisms in driving PASC, enhancement of inflammatory monocyte recruitment via the promotion of CCL2 production, and/or facilitating the development of pro-fibrotic MoAM polarization and differentiation. Additionally, IFN-γ has been recently shown to inhibit alveolar stem cell proliferation directly 53 , and thus it may inhibit the regeneration of alveolar and interstitial tissues through its direct signaling in alveolar epithelial cells following acute SARS-CoV-2 infection.…”

Section: Discussionmentioning

confidence: 99%

Comparative single-cell analysis reveals IFN-γ as a driver of respiratory sequelae post COVID-19

Li,

Qian,

Wei

et al. 2023

Preprint

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Post-acute sequelae of SARS-CoV-2 infection (PASC) represents an urgent public health challenge, with its impact resonating in over 60 million individuals globally. While a growing body of evidence suggests that dysregulated immune reactions may be linked with PASC symptoms, most investigations have primarily centered around blood studies, with few focusing on samples derived from post-COVID affected tissues. Further, clinical studies alone often provide correlative insights rather than causal relationships. Thus, it is essential to compare clinical samples with relevant animal models and conduct functional experiments to truly understand the etiology of PASC. In this study, we have made comprehensive comparisons between bronchoalveolar lavage fluid (BAL) single-cell RNA sequencing (scRNAseq) data derived from clinical PASC samples and relevant PASC mouse models. This revealed a strong pro-fibrotic monocyte-derived macrophage response in respiratory PASC (R-PASC) in both humans and mice, and abnormal interactions between pulmonary macrophages and respiratory resident T cells. IFN-γ emerged as a key node mediating the immune anomalies in R-PASC. Strikingly, neutralizing IFN-γ post the resolution of acute infection reduced lung inflammation, tissue fibrosis, and improved pulmonary gas-exchange function in two mouse models of R-PASC. Our study underscores the importance of performing comparative analysis to understand the root cause of PASC for developing effective therapies.

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“…To model a statistical test, scRNA-seq data from GSE196638, GSE122960, GSE150247, GSE164898 and GSE151177 were used to construct null distributions (H0) of the test. These datasets include scRNA-seq profile from healthy human tissues of lung [13][14][15], skin [16], and breast [17]. To calculate pathway activity, we collected canonical pathways from the KEGG database.…”

Section: Data Sourcementioning

confidence: 99%

“…To model the null distribution of NES in the context of drug response, scRNA-seq data from healthy human tissues of lung, skin and breast were collected [13][14][15][16][17]. Each tissue sample was integrated into a single-cell object using Seurat.…”

Section: Data Processingmentioning

confidence: 99%

scPharm: identifying pharmacological subpopulations of single cells for precision medicine in cancers

Tian,

Zheng,

et al. 2023

Preprint

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Intratumour heterogeneity is a major challenge that limits the effectiveness of anticancer therapies, thus compromising treatment outcomes. Single-cell RNA sequencing (scRNA-seq) technology offers a means to capture gene expression profiles at a single-cell resolution, while drug perturbation experiments yield valuable pharmacological data at the bulk cell level. Here, we introduce “scPharm”, a computational framework to integrate large-scale pharmacogenomics profiles with scRNA-seq data, for identifying pharmacological subpopulations within a tumour and prioritizing tailored drugs. scPharm assesses the distribution of the identity genes of single cell (Cell-ID) within drug response-determined gene list, which is accomplished using the normalized enrichment score (NES) obtained from Gene Set Enrichment Analysis (GSEA). One key strength of scPharm is rooted in the robust positive correlation between NES statistics and drug response values at single-cell resolution. scPharm successfully identifies sensitive subpopulations in ER-positive and HER2-positive human breast cancer tissues, discovers dynamic changes in resistant subpopulation of human PC9 cells treated with Erlotinib, and expands its prediction capabilities to a mouse model. By a thoroughly comparative evaluation with other single-cell prediction tools, scPharm presents the superior predictive performance and computational efficiency. Furthermore, scPharm stands out with its unique capabilities to predict combination strategies, gauging compensation effects or booster effects between two drugs through the Set covering method, as well as to evaluate drug toxicity on healthy cells within the tumour microenvironment. Together, scPharm provides a novel approach to uncover therapeutic heterogeneity within tumours at single-cell resolution and facilitates precision medicine in cancers.

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Dysregulated lung stroma drives emphysema exacerbation by potentiating resident lymphocytes to suppress an epithelial stem cell reservoir

Cited by 32 publications

References 48 publications

Tissue‐resident memory T cells and lung immunopathology

Tissue‐resident memory T cells and lung immunopathology

Comparative single-cell analysis reveals IFN-γ as a driver of respiratory sequelae post COVID-19

scPharm: identifying pharmacological subpopulations of single cells for precision medicine in cancers

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