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Article ; Online: Airway Mucus and Asthma

Luke R. Bonser / David J. Erle

Journal of Clinical Medicine, Vol 6, Iss 12, p

The Role of MUC5AC and MUC5B

2017 Volume 112

Abstract: Asthma is characterized by mucus abnormalities. Airway epithelial hyperplasia and metaplasia result in changes in stored and secreted mucin and the production of a pathologic mucus gel. Mucus transport is impaired, culminating in mucus plugging and ... ...

Abstract	Asthma is characterized by mucus abnormalities. Airway epithelial hyperplasia and metaplasia result in changes in stored and secreted mucin and the production of a pathologic mucus gel. Mucus transport is impaired, culminating in mucus plugging and airway obstruction—a major cause of morbidity in asthma. The polymeric mucins MUC5AC and MUC5B are integral components of airway mucus. MUC5AC and MUC5B gene expression is altered in asthma, and recent work sheds light on their contribution to asthma pathogenesis. Herein, we review our current understanding of the role of MUC5AC and MUC5B in mucus dysfunction in asthma.
Keywords	MUC5AC ; MUC5B ; asthma ; Medicine ; R
Language	English
Publishing date	2017-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: GCLiPP

Wandi S. Zhu / Adam J. Litterman / Harshaan S. Sekhon / Robin Kageyama / Maya M. Arce / Kimberly E. Taylor / Wenxue Zhao / Lindsey A. Criswell / Noah Zaitlen / David J. Erle / K. Mark Ansel

Genome Biology, Vol 24, Iss 1, Pp 1-

global crosslinking and protein purification method for constructing high-resolution occupancy maps for RNA binding proteins

2023 Volume 30

Abstract: Abstract GCLiPP is a global RNA interactome capture method that detects RNA-binding protein (RBP) occupancy transcriptome-wide. GCLiPP maps RBP-occupied sites at a higher resolution than phase separation-based techniques. GCLiPP sequence tags correspond ... ...

Abstract	Abstract GCLiPP is a global RNA interactome capture method that detects RNA-binding protein (RBP) occupancy transcriptome-wide. GCLiPP maps RBP-occupied sites at a higher resolution than phase separation-based techniques. GCLiPP sequence tags correspond with known RBP binding sites and are enriched for sites detected by RBP-specific crosslinking immunoprecipitation (CLIP) for abundant cytosolic RBPs. Comparison of human Jurkat T cells and mouse primary T cells uncovers shared peaks of GCLiPP signal across homologous regions of human and mouse 3′ UTRs, including a conserved mRNA-destabilizing cis-regulatory element. GCLiPP signal overlapping with immune-related SNPs uncovers stabilizing cis-regulatory regions in CD5, STAT6, and IKZF1.
Keywords	Post-transcriptional regulation ; RNA-binding proteins (RBP) ; T cells ; Cis-regulatory elements ; Biology (General) ; QH301-705.5 ; Genetics ; QH426-470
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Chitin-Induced Airway Epithelial Cell Innate Immune Responses Are Inhibited by Carvacrol/Thymol.

Ali Reza Khosravi / David J Erle

PLoS ONE, Vol 11, Iss 7, p e

2016 Volume 0159459

Abstract: Chitin is produced in large amounts by fungi, insects, and other organisms and has been implicated in the pathogenesis of asthma. Airway epithelial cells are in direct contact with environmental particles and serve as the first line of defense against ... ...

Abstract	Chitin is produced in large amounts by fungi, insects, and other organisms and has been implicated in the pathogenesis of asthma. Airway epithelial cells are in direct contact with environmental particles and serve as the first line of defense against inhaled allergens and pathogens. The potential contributions of airway epithelial cells to chitin-induced asthma remain poorly understood. We hypothesized that chitin directly stimulates airway epithelial cells to release cytokines that promote type 2 immune responses and to induce expression of molecules which are important in innate immune responses. We found that chitin exposure rapidly induced the expression of three key type 2-promoting cytokines, IL-25, IL-33 and TSLP, in BEAS-2B transformed human bronchial epithelial cells and in A549 and H292 lung carcinoma cells. Chitin also induced the expression of the key pattern recognition receptors TLR2 and TLR4. Chitin induced the expression of miR-155, miR-146a and miR-21, each of which is known to up-regulate the expression of pro-inflammatory cytokines. Also the expression of SOCS1 and SHIP1 which are known targets of miR-155 was repressed by chitin treatment. The monoterpene phenol carvacrol (Car) and its isomer thymol (Thy) are found in herbal essential oils and have been shown to inhibit allergic inflammation in asthma models. We found that Car/Thy inhibited the effects of chitin on type 2-promoting cytokine release and on the expression of TLRs, SOCS1, SHIP1, and miRNAs. Car/Thy could also efficiently reduce the protein levels of TLR4, inhibit the increase in TLR2 protein levels in chitin plus Car/Thy-treated cells and increase the protein levels of SHIP1 and SOCS1, which are negative regulators of TLR-mediated inflammatory responses. We conclude that direct effects of chitin on airway epithelial cells are likely to contribute to allergic airway diseases like asthma, and that Car/Thy directly inhibits epithelial cell pro-inflammatory responses to chitin.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2016-01-01T00:00:00Z
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: Genomic characterization and therapeutic utilization of IL-13-responsive sequences in asthma

Kyung Duk Koh / Luke R. Bonser / Walter L. Eckalbar / Ofer Yizhar-Barnea / Jiangshan Shen / Xiaoning Zeng / Kirsten L. Hargett / Dingyuan I. Sun / Lorna T. Zlock / Walter E. Finkbeiner / Nadav Ahituv / David J. Erle

Cell Genomics, Vol 3, Iss 1, Pp 100229- (2023)

2023

Abstract: Summary: Epithelial responses to the cytokine interleukin-13 (IL-13) cause airway obstruction in asthma. Here we utilized multiple genomic techniques to identify IL-13-responsive regulatory elements in bronchial epithelial cells and used these data to ... ...

Abstract	Summary: Epithelial responses to the cytokine interleukin-13 (IL-13) cause airway obstruction in asthma. Here we utilized multiple genomic techniques to identify IL-13-responsive regulatory elements in bronchial epithelial cells and used these data to develop a CRISPR interference (CRISPRi)-based therapeutic approach to downregulate airway obstruction-inducing genes in a cell type- and IL-13-specific manner. Using single-cell RNA sequencing (scRNA-seq) and acetylated lysine 27 on histone 3 (H3K27ac) chromatin immunoprecipitation sequencing (ChIP-seq) in primary human bronchial epithelial cells, we identified IL-13-responsive genes and regulatory elements. These sequences were functionally validated and optimized via massively parallel reporter assays (MPRAs) for IL-13-inducible activity. The top secretory cell-selective sequence from the MPRA, a novel, distal enhancer of the sterile alpha motif pointed domain containing E-26 transformation-specific transcription factor (SPDEF) gene, was utilized to drive CRISPRi and knock down SPDEF or mucin 5AC (MUC5AC), both involved in pathologic mucus production in asthma. Our work provides a catalog of cell type-specific genes and regulatory elements involved in IL-13 bronchial epithelial response and showcases their use for therapeutic purposes.
Keywords	enhancer ; IL-13 ; cell-specific ; CRISPRi ; HBEC ; SPDEF ; Genetics ; QH426-470 ; Internal medicine ; RC31-1245
Subject code	572
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Comparison of Reproducibility, Accuracy, Sensitivity, and Specificity of miRNA Quantification Platforms

Paula M. Godoy / Andrea J. Barczak / Peter DeHoff / Srimeenakshi Srinivasan / Alton Etheridge / David Galas / Saumya Das / David J. Erle / Louise C. Laurent

Cell Reports, Vol 29, Iss 12, Pp 4212-4222.e

2019 Volume 5

Abstract: Summary: Given the increasing interest in their use as disease biomarkers, the establishment of reproducible, accurate, sensitive, and specific platforms for microRNA (miRNA) quantification in biofluids is of high priority. We compare four platforms for ... ...

Abstract	Summary: Given the increasing interest in their use as disease biomarkers, the establishment of reproducible, accurate, sensitive, and specific platforms for microRNA (miRNA) quantification in biofluids is of high priority. We compare four platforms for these characteristics: small RNA sequencing (RNA-seq), FirePlex, EdgeSeq, and nCounter. For a pool of synthetic miRNAs, coefficients of variation for technical replicates are lower for EdgeSeq (6.9%) and RNA-seq (8.2%) than for FirePlex (22.4%); nCounter replicates are not performed. Receiver operating characteristic analysis for distinguishing present versus absent miRNAs shows small RNA-seq (area under curve 0.99) is superior to EdgeSeq (0.97), nCounter (0.94), and FirePlex (0.81). Expected differences in expression of placenta-associated miRNAs in plasma from pregnant and non-pregnant women are observed with RNA-seq and EdgeSeq, but not FirePlex or nCounter. These results indicate that differences in performance among miRNA profiling platforms impact ability to detect biological differences among samples and thus their relative utility for research and clinical use. : Using pools of synthetic RNA oligonucleotides and standardized extracellular RNA samples, Godoy et al. compare small RNA sequencing to three targeted miRNA quantification platforms to evaluate reproducibility, bias, specificity and sensitivity, and accuracy. Each platform has strengths and limitations important to consider for biomarker discovery, clinical validation, and broad clinical use. Keywords: small RNA-sequencing, HTG Molecular EdgeSeq, Abcam FirePlex, NanoString nCounter, miRNA quantification, extracellular RNA
Keywords	Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2019-12-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Epithelial miR-141 regulates IL-13–induced airway mucus production

Sana Siddiqui / Kristina Johansson / Alex Joo / Luke R. Bonser / Kyung Duk Koh / Olivier Le Tonqueze / Samaneh Bolourchi / Rodriel A. Bautista / Lorna Zlock / Theodore L. Roth / Alexander Marson / Nirav R. Bhakta / K. Mark Ansel / Walter E. Finkbeiner / David J. Erle / Prescott G. Woodruff

JCI Insight, Vol 6, Iss

2021 Volume 5

Abstract: IL-13–induced goblet cell metaplasia contributes to airway remodeling and pathological mucus hypersecretion in asthma. miRNAs are potent modulators of cellular responses, but their role in mucus regulation is largely unexplored. We hypothesized that ... ...

Abstract	IL-13–induced goblet cell metaplasia contributes to airway remodeling and pathological mucus hypersecretion in asthma. miRNAs are potent modulators of cellular responses, but their role in mucus regulation is largely unexplored. We hypothesized that airway epithelial miRNAs play roles in IL-13–induced mucus regulation. miR-141 is highly expressed in human and mouse airway epithelium, is altered in bronchial brushings from asthmatic subjects at baseline, and is induced shortly after airway allergen exposure. We established a CRISPR/Cas9-based protocol to target miR-141 in primary human bronchial epithelial cells that were differentiated at air-liquid-interface, and goblet cell hyperplasia was induced by IL-13 stimulation. miR-141 disruption resulted in decreased goblet cell frequency, intracellular MUC5AC, and total secreted mucus. These effects correlated with a reduction in a goblet cell gene expression signature and enrichment of a basal cell gene expression signature defined by single cell RNA sequencing. Furthermore, intranasal administration of a sequence-specific mmu-miR-141-3p inhibitor in mice decreased Aspergillus-induced secreted mucus and mucus-producing cells in the lung and reduced airway hyperresponsiveness without affecting cellular inflammation. In conclusion, we have identified a miRNA that regulates pathological airway mucus production and is amenable to therapeutic manipulation through an inhaled route.
Keywords	Pulmonology ; Medicine ; R
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Spontaneous Chitin Accumulation in Airways and Age-Related Fibrotic Lung Disease

Van Dyken, Steven J / David J. Erle / Hong-Erh Liang / Paul J. Wolters / Prescott G. Woodruff / Ram P. Naikawadi / Richard M. Locksley

Cell. 2017 Apr. 20, v. 169

2017

Abstract: The environmentally widespread polysaccharide chitin is degraded and recycled by ubiquitous bacterial and fungal chitinases. Although vertebrates express active chitinases from evolutionarily conserved loci, their role in mammalian physiology is unclear. ...

Abstract	The environmentally widespread polysaccharide chitin is degraded and recycled by ubiquitous bacterial and fungal chitinases. Although vertebrates express active chitinases from evolutionarily conserved loci, their role in mammalian physiology is unclear. We show that distinct lung epithelial cells secrete acidic mammalian chitinase (AMCase), which is required for airway chitinase activity. AMCase-deficient mice exhibit premature morbidity and mortality, concomitant with accumulation of environmentally derived chitin polymers in the airways and expression of pro-fibrotic cytokines. Over time, these mice develop spontaneous pulmonary fibrosis, which is ameliorated by restoration of lung chitinase activity by genetic or therapeutic approaches. AMCase-deficientÂ epithelial cells express fibrosis-associated gene sets linked with cell stress pathways. Mice with lung fibrosis due to telomere dysfunction and humans with interstitial lung disease also accumulate excess chitin polymers in their airways. These data suggest that altered chitin clearance could exacerbate fibrogenic pathways in the setting of lung diseases characterized by epithelial cell dysfunction.
Keywords	chitin ; chitinase ; cytokines ; epithelial cells ; fibrosis ; fungi ; genes ; humans ; loci ; mice ; morbidity ; mortality ; physiology ; polymers ; respiratory tract diseases ; telomeres
Language	English
Dates of publication	2017-0420
Size	p. 497-509.e13.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2017.03.044
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Features of acute COVID-19 associated with post-acute sequelae of SARS-CoV-2 phenotypes

Al Ozonoff / Naresh Doni Jayavelu / Shanshan Liu / Esther Melamed / Carly E. Milliren / Jingjing Qi / Linda N. Geng / Grace A. McComsey / Charles B. Cairns / Lindsey R. Baden / Joanna Schaenman / Albert C. Shaw / Hady Samaha / Vicki Seyfert-Margolis / Florian Krammer / Lindsey B. Rosen / Hanno Steen / Caitlin Syphurs / Ravi Dandekar /

Casey P. Shannon / Rafick P. Sekaly / Lauren I. R. Ehrlich / David B. Corry / Farrah Kheradmand / Mark A. Atkinson / Scott C. Brakenridge / Nelson I. Agudelo Higuita / Jordan P. Metcalf / Catherine L. Hough / William B. Messer / Bali Pulendran / Kari C. Nadeau / Mark M. Davis / Ana Fernandez Sesma / Viviana Simon / Harm van Bakel / Seunghee Kim-Schulze / David A. Hafler / Ofer Levy / Monica Kraft / Chris Bime / Elias K. Haddad / Carolyn S. Calfee / David J. Erle / Charles R. Langelier / Walter Eckalbar / Steven E. Bosinger / IMPACC Network / Bjoern Peters / Steven H. Kleinstein / Elaine F. Reed / Alison D. Augustine / Joann Diray-Arce / Holden T. Maecker / Matthew C. Altman / Ruth R. Montgomery / Patrice M. Becker / Nadine Rouphael

Nature Communications, Vol 15, Iss 1, Pp 1-

results from the IMPACC study

2024 Volume 17

Abstract: Abstract Post-acute sequelae of SARS-CoV-2 (PASC) is a significant public health concern. We describe Patient Reported Outcomes (PROs) on 590 participants prospectively assessed from hospital admission for COVID-19 through one year after discharge. ... ...

Abstract	Abstract Post-acute sequelae of SARS-CoV-2 (PASC) is a significant public health concern. We describe Patient Reported Outcomes (PROs) on 590 participants prospectively assessed from hospital admission for COVID-19 through one year after discharge. Modeling identified 4 PRO clusters based on reported deficits (minimal, physical, mental/cognitive, and multidomain), supporting heterogenous clinical presentations in PASC, with sub-phenotypes associated with female sex and distinctive comorbidities. During the acute phase of disease, a higher respiratory SARS-CoV-2 viral burden and lower Receptor Binding Domain and Spike antibody titers were associated with both the physical predominant and the multidomain deficit clusters. A lower frequency of circulating B lymphocytes by mass cytometry (CyTOF) was observed in the multidomain deficit cluster. Circulating fibroblast growth factor 21 (FGF21) was significantly elevated in the mental/cognitive predominant and the multidomain clusters. Future efforts to link PASC to acute anti-viral host responses may help to better target treatment and prevention of PASC.
Keywords	Science ; Q
Language	English
Publishing date	2024-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Tonic LAT-HDAC7 Signals Sustain Nur77 and Irf4 Expression to Tune Naive CD4 T Cells

Darienne R. Myers / Tannia Lau / Evan Markegard / Hyung W. Lim / Herbert Kasler / Minghua Zhu / Andrea Barczak / John P. Huizar / Julie Zikherman / David J. Erle / Weiguo Zhang / Eric Verdin / Jeroen P. Roose

Cell Reports, Vol 19, Iss 8, Pp 1558-

2017 Volume 1571

Abstract: CD4+ T cells differentiate into T helper cell subsets in feedforward manners with synergistic signals from the T cell receptor (TCR), cytokines, and lineage-specific transcription factors. Naive CD4+ T cells avoid spontaneous engagement of feedforward ... ...

Abstract	CD4+ T cells differentiate into T helper cell subsets in feedforward manners with synergistic signals from the T cell receptor (TCR), cytokines, and lineage-specific transcription factors. Naive CD4+ T cells avoid spontaneous engagement of feedforward mechanisms but retain a prepared state. T cells lacking the adaptor molecule LAT demonstrate impaired TCR-induced signals yet cause a spontaneous lymphoproliferative T helper 2 (TH2) cell syndrome in mice. Thus, LAT constitutes an unexplained maintenance cue. Here, we demonstrate that tonic signals through LAT constitutively export the repressor HDAC7 from the nucleus of CD4+ T cells. Without such tonic signals, HDAC7 target genes Nur77 and Irf4 are repressed. We reveal that Nur77 suppresses CD4+ T cell proliferation and uncover a suppressive role for Irf4 in TH2 polarization; halving Irf4 gene-dosage leads to increases in GATA3+ and IL-4+ cells. Our studies reveal that naive CD4+ T cells are dynamically tuned by tonic LAT-HDAC7 signals.
Keywords	tonic signals ; T cells ; LAT ; HDAC ; gene expression ; Th2 ; Nur77 ; Irf4 ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2017-05-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Identification of MiR-205 As a MicroRNA That Is Highly Expressed in Medullary Thymic Epithelial Cells.

Imran S Khan / Chong Y Park / Anastasia Mavropoulos / Nikki Shariat / Joshua L Pollack / Andrea J Barczak / David J Erle / Michael T McManus / Mark S Anderson / Lukas T Jeker

PLoS ONE, Vol 10, Iss 8, p e

2015 Volume 0135440

Abstract: Thymic epithelial cells (TECs) support T cell development in the thymus. Cortical thymic epithelial cells (cTECs) facilitate positive selection of developing thymocytes whereas medullary thymic epithelial cells (mTECs) facilitate the deletion of self- ... ...

Abstract	Thymic epithelial cells (TECs) support T cell development in the thymus. Cortical thymic epithelial cells (cTECs) facilitate positive selection of developing thymocytes whereas medullary thymic epithelial cells (mTECs) facilitate the deletion of self-reactive thymocytes in order to prevent autoimmunity. The mTEC compartment is highly dynamic with continuous maturation and turnover, but the genetic regulation of these processes remains poorly understood. MicroRNAs (miRNAs) are important regulators of TEC genetic programs since miRNA-deficient TECs are severely defective. However, the individual miRNAs important for TEC maintenance and function and their mechanisms of action remain unknown. Here, we demonstrate that miR-205 is highly and preferentially expressed in mTECs during both thymic ontogeny and in the postnatal thymus. This distinct expression is suggestive of functional importance for TEC biology. Genetic ablation of miR-205 in TECs, however, neither revealed a role for miR-205 in TEC function during homeostatic conditions nor during recovery from thymic stress conditions. Thus, despite its distinct expression, miR-205 on its own is largely dispensable for mTEC biology.
Keywords	Medicine ; R ; Science ; Q
Subject code	500
Language	English
Publishing date	2015-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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