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Article ; Online: Loss of Fas signaling in fibroblasts impairs homeostatic fibrosis resolution and promotes persistent pulmonary fibrosis

Elizabeth F. Redente / Sangeeta Chakraborty / Satria Sajuthi / Bart P. Black / Ben L. Edelman / Max A. Seibold / David W.H. Riches

JCI Insight, Vol 6, Iss

2021 Volume 1

Abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible fibrotic disease of the distal lung alveoli that culminates in respiratory failure and reduced lifespan. Unlike normal lung repair in response to injury, IPF is associated with the ... ...

Abstract	Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible fibrotic disease of the distal lung alveoli that culminates in respiratory failure and reduced lifespan. Unlike normal lung repair in response to injury, IPF is associated with the accumulation and persistence of fibroblasts and myofibroblasts, as well as continued production of collagen and other extracellular matrix (ECM) components. Prior in vitro studies have led to the hypothesis that the development of resistance to Fas-induced apoptosis by lung fibroblasts and myofibroblasts contributes to their accumulation in the distal lung tissues of IPF patients. Here, we test this hypothesis in vivo in the resolving model of bleomycin-induced pulmonary fibrosis in mice. Using genetic loss-of-function approaches to inhibit Fas signaling in fibroblasts, potentially novel flow cytometry strategies to quantify lung fibroblast subsets, and transcriptional profiling of lung fibroblasts by bulk and single cell RNA sequencing, we show that Fas is necessary for lung fibroblast apoptosis during homeostatic resolution of bleomycin-induced pulmonary fibrosis in vivo. Furthermore, we show that loss of Fas signaling leads to the persistence and continued profibrotic functions of lung fibroblasts. Our studies provide insights into the mechanisms that contribute to fibroblast survival, persistence, and continued ECM deposition in the context of IPF and how failure to undergo Fas-induced apoptosis impairs fibrosis resolution.
Keywords	Pulmonology ; Medicine ; R
Subject code	610
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: IL-13–programmed airway tuft cells produce PGE2, which promotes CFTR-dependent mucociliary function

Maya E. Kotas / Camille M. Moore / Jose G. Gurrola II / Steven D. Pletcher / Andrew N. Goldberg / Raquel Alvarez / Sheyla Yamato / Preston E. Bratcher / Ciaran A. Shaughnessy / Pamela L. Zeitlin / Irene H. Zhang / Yingchun Li / Michael T. Montgomery / Keehoon Lee / Emily K. Cope / Richard M. Locksley / Max A. Seibold / Erin D. Gordon

JCI Insight, Vol 7, Iss

2022 Volume 13

Abstract: Chronic type 2 (T2) inflammatory diseases of the respiratory tract are characterized by mucus overproduction and disordered mucociliary function, which are largely attributed to the effects of IL-13 on common epithelial cell types (mucus secretory and ... ...

Abstract	Chronic type 2 (T2) inflammatory diseases of the respiratory tract are characterized by mucus overproduction and disordered mucociliary function, which are largely attributed to the effects of IL-13 on common epithelial cell types (mucus secretory and ciliated cells). The role of rare cells in airway T2 inflammation is less clear, though tuft cells have been shown to be critical in the initiation of T2 immunity in the intestine. Using bulk and single-cell RNA sequencing of airway epithelium and mouse modeling, we found that IL-13 expanded and programmed airway tuft cells toward eicosanoid metabolism and that tuft cell deficiency led to a reduction in airway prostaglandin E2 (PGE2) concentration. Allergic airway epithelia bore a signature of PGE2 activation, and PGE2 activation led to cystic fibrosis transmembrane receptor–dependent ion and fluid secretion and accelerated mucociliary transport. These data reveal a role for tuft cells in regulating epithelial mucociliary function in the allergic airway.
Keywords	Inflammation ; Pulmonology ; Medicine ; R
Subject code	610
Language	English
Publishing date	2022-07-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Dissecting the cellular specificity of smoking effects and reconstructing lineages in the human airway epithelium

Katherine C. Goldfarbmuren / Nathan D. Jackson / Satria P. Sajuthi / Nathan Dyjack / Katie S. Li / Cydney L. Rios / Elizabeth G. Plender / Michael T. Montgomery / Jamie L. Everman / Preston E. Bratcher / Eszter K. Vladar / Max A. Seibold

Nature Communications, Vol 11, Iss 1, Pp 1-

2020 Volume 21

Abstract: Chronic lung diseases are characterized by molecular and cellular composition changes. Here the authors use single-cell RNA sequencing to map cell type-specific changes in human tracheal epithelium related to smoking, and to provide evidence for a tuft- ... ...

Abstract	Chronic lung diseases are characterized by molecular and cellular composition changes. Here the authors use single-cell RNA sequencing to map cell type-specific changes in human tracheal epithelium related to smoking, and to provide evidence for a tuft-like progenitor for pulmonary neuroendocrine cells and ionocytes.
Keywords	Science ; Q
Language	English
Publishing date	2020-05-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Single cell analysis of host response to helminth infection reveals the clonal breadth, heterogeneity, and tissue-specific programming of the responding CD4+ T cell repertoire.

Ivy K Brown / Nathan Dyjack / Mindy M Miller / Harsha Krovi / Cydney Rios / Rachel Woolaver / Laura Harmacek / Ting-Hui Tu / Brian P O'Connor / Thomas Danhorn / Brian Vestal / Laurent Gapin / Clemencia Pinilla / Max A Seibold / James Scott-Browne / Radleigh G Santos / R Lee Reinhardt

PLoS Pathogens, Vol 17, Iss 6, p e

2021 Volume 1009602

Abstract: The CD4+ T cell response is critical to host protection against helminth infection. How this response varies across different hosts and tissues remains an important gap in our understanding. Using IL-4-reporter mice to identify responding CD4+ T cells to ...

Abstract	The CD4+ T cell response is critical to host protection against helminth infection. How this response varies across different hosts and tissues remains an important gap in our understanding. Using IL-4-reporter mice to identify responding CD4+ T cells to Nippostrongylus brasiliensis infection, T cell receptor sequencing paired with novel clustering algorithms revealed a broadly reactive and clonally diverse CD4+ T cell response. While the most prevalent clones and clonotypes exhibited some tissue selectivity, most were observed to reside in both the lung and lung-draining lymph nodes. Antigen-reactivity of the broader repertoires was predicted to be shared across both tissues and individual mice. Transcriptome, trajectory, and chromatin accessibility analysis of lung and lymph-node repertoires revealed three unique but related populations of responding IL-4+ CD4+ T cells consistent with T follicular helper, T helper 2, and a transitional population sharing similarity with both populations. The shared antigen reactivity of lymph node and lung repertoires combined with the adoption of tissue-specific gene programs allows for the pairing of cellular and humoral responses critical to the orchestration of anti-helminth immunity.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2021-06-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Nasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology

Satria P. Sajuthi / Jamie L. Everman / Nathan D. Jackson / Benjamin Saef / Cydney L. Rios / Camille M. Moore / Angel C. Y. Mak / Celeste Eng / Ana Fairbanks-Mahnke / Sandra Salazar / Jennifer Elhawary / Scott Huntsman / Vivian Medina / Deborah A. Nickerson / Soren Germer / Michael C. Zody / Gonçalo Abecasis / Hyun Min Kang / Kenneth M. Rice /

Rajesh Kumar / Noah A. Zaitlen / Sam Oh / NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium / José Rodríguez-Santana / Esteban G. Burchard / Max A. Seibold

Nature Communications, Vol 13, Iss 1, Pp 1-

2022 Volume 17

Abstract: Understanding regulation of genes associated to disease can reveal insights into disease mechanisms. Here, the authors perform an airway epithelial transcriptome-wide association analysis to elucidate genetic determinants of airway dysfunction in asthma, ...

Abstract	Understanding regulation of genes associated to disease can reveal insights into disease mechanisms. Here, the authors perform an airway epithelial transcriptome-wide association analysis to elucidate genetic determinants of airway dysfunction in asthma, identifying genetic mechanisms of mucus pathobiology.
Keywords	Science ; Q
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Differential asthma odds following respiratory infection in children from three minority populations.

Eric M Wohlford / Luisa N Borrell / Jennifer R Elhawary / Brian Plotkin / Sam S Oh / Thomas J Nuckton / Celeste Eng / Sandra Salazar / Michael A LeNoir / Kelley Meade / Harold J Farber / Denise Serebrisky / Emerita Brigino-Buenaventura / William Rodriguez-Cintron / Rajesh Kumar / Shannon Thyne / Max A Seibold / José R Rodríguez-Santana / Esteban G Burchard

PLoS ONE, Vol 15, Iss 5, p e

2020 Volume 0231782

Abstract: Rationale Severe early-life respiratory illnesses, particularly those caused by respiratory syncytial virus (RSV) and human rhinovirus (HRV), are strongly associated with the development of asthma in children. Puerto Rican children in particular have a ... ...

Abstract	Rationale Severe early-life respiratory illnesses, particularly those caused by respiratory syncytial virus (RSV) and human rhinovirus (HRV), are strongly associated with the development of asthma in children. Puerto Rican children in particular have a strikingly high asthma burden. However, prior studies of the potential associations between early-life respiratory illnesses and asthma in Puerto Rican and other minority populations have been limited. Objectives We sought to determine whether early-life respiratory illness was associated with asthma in Puerto Rican, Mexican American, and African American children. Methods Using a logistic regression analysis, we examined the association between early-life respiratory illnesses (report of upper respiratory infection (URI), pneumonia, bronchitis, and bronchiolitis/RSV) within the first two years of life and physician-diagnosed asthma after the age of two in a large cohort of Puerto Rican, Mexican American, and African American children. Measurements and main results While early-life respiratory illnesses were associated with greater asthma odds in Puerto Ricans, Mexican Americans, and African Americans, these associations were stronger among Puerto Rican children. Specifically, in Puerto Ricans, the odds was 6.15 (95% CI: 4.21-9.05) if the child reported at least one of the following respiratory illness: URI, pneumonia, bronchitis or bronchiolitis. The odds were also higher in Puerto Ricans when considering these conditions separately. Conclusions We observed population-specific associations between early-life respiratory illnesses and asthma, which were especially significant and stronger in Puerto Ricans. Taken together with the known high burden of RSV in Puerto Rico, our results may help explain the high burden of asthma in Puerto Ricans.
Keywords	Medicine ; R ; Science ; Q
Subject code	420
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Meta-analysis of peripheral blood gene expression modules for COPD phenotypes.

Dominik Reinhold / Jarrett D Morrow / Sean Jacobson / Junxiao Hu / Benjamin Ringel / Max A Seibold / Craig P Hersh / Katerina J Kechris / Russell P Bowler

PLoS ONE, Vol 12, Iss 10, p e

2017 Volume 0185682

Abstract: Chronic obstructive pulmonary disease (COPD) occurs typically in current or former smokers, but only a minority of people with smoking history develops the disease. Besides environmental factors, genetics is an important risk factor for COPD. However, ... ...

Abstract	Chronic obstructive pulmonary disease (COPD) occurs typically in current or former smokers, but only a minority of people with smoking history develops the disease. Besides environmental factors, genetics is an important risk factor for COPD. However, the relationship between genetics, environment and phenotypes is not well understood. Sample sizes for genome-wide expression studies based on lung tissue have been small due to the invasive nature of sample collection. Increasing evidence for the systemic nature of the disease makes blood a good alternative source to study the disease, but there have also been few large-scale blood genomic studies in COPD. Due to the complexity and heterogeneity of COPD, examining groups of interacting genes may have more relevance than identifying individual genes. Therefore, we used Weighted Gene Co-expression Network Analysis to find groups of genes (modules) that are highly connected. However, module definitions may vary between individual data sets. To alleviate this problem, we used a consensus module definition based on two cohorts, COPDGene and ECLIPSE. We studied the relationship between the consensus modules and COPD phenotypes airflow obstruction and emphysema. We also used these consensus module definitions on an independent cohort (TESRA) and performed a meta analysis involving all data sets. We found several modules that are associated with COPD phenotypes, are enriched in functional categories and are overrepresented for cell-type specific genes. Of the 14 consensus modules, three were strongly associated with airflow obstruction (meta p ≤ 0.0002), and two had some association with emphysema (meta p ≤ 0.06); some associations were stronger in the case-control cohorts, and others in the cases-only subcohorts. Gene Ontology terms that were overrepresented included "immune response" and "defense response." The cell types whose type-specific genes were overrepresented in modules (p < 0.05) included natural killer cells, dendritic cells, and neutrophils. Together, this is the largest investigation of gene blood expression in COPD with 469 cases in COPDGene, ECLIPSE and TESRA combined, with 6267 genes common to all data sets. Additional, we have 42 and 83 controls in COPDGene and ECLIPSE, respectively.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2017-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Lipid abnormalities in atopic skin are driven by type 2 cytokines

Evgeny Berdyshev / Elena Goleva / Irina Bronova / Nathan Dyjack / Cydney Rios / John Jung / Patricia Taylor / Mingeum Jeong / Clifton F. Hall / Brittany N. Richers / Kathryn A. Norquest / Tao Zheng / Max A. Seibold / Donald Y.M. Leung

JCI Insight, Vol 3, Iss

2018 Volume 4

Abstract: Lipids in the stratum corneum of atopic dermatitis (AD) patients differ substantially in composition from healthy subjects. We hypothesized that hyperactivated type 2 immune response alters AD skin lipid metabolism. We have analyzed stratum corneum ... ...

Abstract	Lipids in the stratum corneum of atopic dermatitis (AD) patients differ substantially in composition from healthy subjects. We hypothesized that hyperactivated type 2 immune response alters AD skin lipid metabolism. We have analyzed stratum corneum lipids from nonlesional and lesional skin of AD subjects and IL-13 skin-specific Tg mice. We also directly examined the effects of IL-4/IL-13 on human keratinocytes in vitro. Mass spectrometric analysis of lesional stratum corneum from AD subjects and IL-13 Tg mice revealed an increased proportion of short-chain (N-14:0 to N-24:0) NS ceramides, sphingomyelins, and 14:0–22:0 lysophosphatidylcholines (14:0–22:0 LPC) with a simultaneous decline in the proportion of corresponding long-chain species (N-26:0 to N-32:0 sphingolipids and 24:0–30:0 LPC) when compared with healthy controls. An increase in short-chain LPC species was also observed in nonlesional AD skin. Similar changes were observed in IL-4/IL-13–driven responses in Ca2+-differentiated human keratinocytes in vitro, all being blocked by STAT6 silencing with siRNA. RNA sequencing analysis performed on stratum corneum of AD as compared with healthy subjects identified decreased expression of fatty acid elongases ELOVL3 and ELOVL6 that contributed to observed changes in atopic skin lipids. IL-4/IL-13 also inhibited ELOVL3 and ELOVL6 expression in keratinocyte cultures in a STAT6-dependent manner. Downregulation of ELOVL3/ELOVL6 expression in keratinocytes by siRNA decreased the proportion of long-chain fatty acids globally and in sphingolipids. Thus, our data strongly support the pathogenic role of type 2 immune activation in AD skin lipid metabolism.
Keywords	Dermatology ; Medicine ; R
Subject code	571
Language	English
Publishing date	2018-02-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Correction to

Agata Wesolowska-Andersen / Jamie L. Everman / Rebecca Davidson / Cydney Rios / Rachelle Herrin / Celeste Eng / William J. Janssen / Andrew H. Liu / Sam S. Oh / Rajesh Kumar / Tasha E. Fingerlin / Jose Rodriguez-Santana / Esteban G. Burchard / Max A. Seibold

Genome Biology, Vol 19, Iss 1, Pp 1-

Dual RNA-seq reveals viral infections in asthmatic children without respiratory illness which are associated with changes in the airway transcriptome

2018 Volume 1

Abstract: Abstract In our recent article [1], it has come to our attention that the sample labels are not consistent between Table 1, the data labels deposited in the Sequence Read Archive, and Additional file 1: Table S2. We are therefore providing an updated ... ...

Abstract	Abstract In our recent article [1], it has come to our attention that the sample labels are not consistent between Table 1, the data labels deposited in the Sequence Read Archive, and Additional file 1: Table S2. We are therefore providing an updated Additional file 1: Table S2 so identical samples now have the same label.
Keywords	Biology (General) ; QH301-705.5 ; Genetics ; QH426-470
Language	English
Publishing date	2018-04-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Dual RNA-seq reveals viral infections in asthmatic children without respiratory illness which are associated with changes in the airway transcriptome

Genome Biology, Vol 18, Iss 1, Pp 1-

2017 Volume 17

Abstract: Abstract Background Respiratory illness caused by viral infection is associated with the development and exacerbation of childhood asthma. Little is known about the effects of respiratory viral infections in the absence of illness. Using quantitative PCR ...

Abstract	Abstract Background Respiratory illness caused by viral infection is associated with the development and exacerbation of childhood asthma. Little is known about the effects of respiratory viral infections in the absence of illness. Using quantitative PCR (qPCR) for common respiratory viruses and for two genes known to be highly upregulated in viral infections (CCL8/CXCL11), we screened 92 asthmatic and 69 healthy children without illness for respiratory virus infections. Results We found 21 viral qPCR-positive and 2 suspected virus-infected subjects with high expression of CCL8/CXCL11. We applied a dual RNA-seq workflow to these subjects, together with 25 viral qPCR-negative subjects, to compare qPCR with sequencing-based virus detection and to generate the airway transcriptome for analysis. RNA-seq virus detection achieved 86% sensitivity when compared to qPCR-based screening. We detected additional respiratory viruses in the two CCL8/CXCL11-high subjects and in two of the qPCR-negative subjects. Viral read counts varied widely and were used to stratify subjects into Virus-High and Virus-Low groups. Examination of the host airway transcriptome found that the Virus-High group was characterized by immune cell airway infiltration, downregulation of cilia genes, and dampening of type 2 inflammation. Even the Virus-Low group was differentiated from the No-Virus group by 100 genes, some involved in eIF2 signaling. Conclusions Respiratory virus infection without illness is not innocuous but may determine the airway function of these subjects by driving immune cell airway infiltration, cellular remodeling, and alteration of asthmogenic gene expression.
Keywords	Asymptomatic ; Virus ; Infection ; Transcriptome ; Airway epithelium ; RNA-seq ; Biology (General) ; QH301-705.5 ; Genetics ; QH426-470
Subject code	570
Language	English
Publishing date	2017-01-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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