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Lew SQ, Chong SY, Lau GW. Modulation of pulmonary immune functions by the Pseudomonas aeruginosa secondary metabolite pyocyanin. Front Immunol 2025; 16:1550724. [PMID: 40196115 PMCID: PMC11973339 DOI: 10.3389/fimmu.2025.1550724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 03/05/2025] [Indexed: 04/09/2025] Open
Abstract
Pseudomonas aeruginosa is a prevalent opportunistic Gram-negative bacterial pathogen. One of its key virulence factors is pyocyanin, a redox-active phenazine secondary metabolite that plays a crucial role in the establishment and persistence of chronic infections. This review provides a synopsis of the mechanisms through which pyocyanin exacerbates pulmonary infections. Pyocyanin induces oxidative stress by generating reactive oxygen and nitrogen species which disrupt essential defense mechanisms in respiratory epithelium. Pyocyanin increases airway barrier permeability and facilitates bacterial invasion. Pyocyanin also impairs mucociliary clearance by damaging ciliary function, resulting in mucus accumulation and airway obstruction. Furthermore, it modulates immune responses by promoting the production of pro-inflammatory cytokines, accelerating neutrophil apoptosis, and inducing excessive neutrophil extracellular trap formation, which exacerbates lung tissue damage. Additionally, pyocyanin disrupts macrophage phagocytic function, hindering the clearance of apoptotic cells and perpetuating inflammation. It also triggers mucus hypersecretion by inactivating the transcription factor FOXA2 and enhancing the IL-4/IL-13-STAT6 and EGFR-AKT/ERK1/2 signaling pathways, leading to goblet cell metaplasia and increased mucin production. Insights into the role of pyocyanin in P. aeruginosa infections may reveal potential therapeutic strategies to alleviate the severity of infections in chronic respiratory diseases including cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD).
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Affiliation(s)
| | | | - Gee W. Lau
- Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL, United States
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2
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Fotook Kiaei SZ, Schwartz DA. Genetic underpinning of idiopathic pulmonary fibrosis: the role of mucin. Expert Rev Respir Med 2025:1-12. [PMID: 39912527 DOI: 10.1080/17476348.2025.2464035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 12/27/2024] [Accepted: 02/04/2025] [Indexed: 02/07/2025]
Abstract
INTRODUCTION Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by progressive scarring and reduced survival. The development of IPF is influenced by rare and common genetic variants, cigarette smoking, aging, and environmental exposures. Among the two dozen genetic contributors, the MUC5B promoter variant (rs35705950) is the dominant risk factor, increasing the risk of both familial and sporadic IPF and accounting for nearly 50% of the genetic predisposition to the disease. AREAS COVERED This review provides an expert perspective on the genetic underpinnings of IPF rather than a systematic analysis, emphasizing key insights into its genetic basis. The articles referenced in this review were identified through targeted searches in PubMed, Scopus, and Web of Science for studies published between 2000 and 2023, prioritizing influential research on the genetic factors contributing to IPF. Search terms included 'idiopathic pulmonary fibrosis,' 'genetics,' 'MUC5B,' 'telomere dysfunction,' and 'surfactant proteins.' The selection of studies was guided by the authors' expertise, focusing on the most relevant publications. EXPERT OPINION The identification of genetic variants not only highlights the complexity of IPF but also offers potential for earlier diagnosis and personalized treatment strategies targeting specific genetic pathways, ultimately aiming to improve patient outcomes.
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Affiliation(s)
| | - David A Schwartz
- Department of Medicine, University of Colorado Denver, School of Medicine, Aurora, CO, USA
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Bigliardi E, Shetty AV, Low WC, Steer CJ. Interspecies Blastocyst Complementation and the Genesis of Chimeric Solid Human Organs. Genes (Basel) 2025; 16:215. [PMID: 40004544 PMCID: PMC11854981 DOI: 10.3390/genes16020215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 02/06/2025] [Accepted: 02/09/2025] [Indexed: 02/27/2025] Open
Abstract
Solid organ transplantation remains a life-saving treatment for patients worldwide. Unfortunately, the supply of donor organs cannot meet the current need, making the search for alternative sources even more essential. Xenotransplantation using sophisticated genetic engineering techniques to delete and overexpress specific genes in the donor animal has been investigated as a possible option. However, the use of exogenous tissue presents another host of obstacles, particularly regarding organ rejection. Given these limitations, interspecies blastocyst complementation in combination with precise gene knockouts presents a unique, promising pathway for the transplant organ shortage. In recent years, great advancements have been made in the field, with encouraging results in producing a donor-derived organ in a chimeric host. That said, one of the major barriers to successful interspecies chimerism is the mismatch in the developmental stages of the donor and the host cells in the chimeric embryo. Another major barrier to successful chimerism is the mismatch in the developmental speeds between the donor and host cells in the chimeric embryos. This review outlines 19 studies in which blastocyst complementation was used to generate solid organs. In particular, the genesis of the liver, lung, kidney, pancreas, heart, thyroid, thymus and parathyroids was investigated. Of the 19 studies, 7 included an interspecies model. Of the 7, one was completed using human donor cells in a pig host, and all others were rat-mouse chimeras. While very promising results have been demonstrated, with great advancements in the field, several challenges continue to persist. In particular, successful chimerism, organ generation and donor contribution, synchronized donor-host development, as well as ethical concerns regarding human-animal chimeras remain important aspects that will need to be addressed in future research.
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Affiliation(s)
- Elena Bigliardi
- Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA;
| | - Anala V. Shetty
- Molecular, Cellular, Developmental Biology, and Genetics Graduate Program, University of Minnesota, Minneapolis, MN 55455, USA;
- Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA
| | - Walter C. Low
- Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA;
- Molecular, Cellular, Developmental Biology, and Genetics Graduate Program, University of Minnesota, Minneapolis, MN 55455, USA;
- Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA
| | - Clifford J. Steer
- Molecular, Cellular, Developmental Biology, and Genetics Graduate Program, University of Minnesota, Minneapolis, MN 55455, USA;
- Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
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Baraldi F, Bigoni T, Foschino Barbaro MP, Micheletto C, Scioscia G, Vatrella A, Papi A. Mucus production and chronic obstructive pulmonary disease, a possible treatment target: zooming in on N-acetylcysteine. Monaldi Arch Chest Dis 2025. [PMID: 39810570 DOI: 10.4081/monaldi.2025.3159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 10/28/2024] [Indexed: 01/16/2025] Open
Abstract
Mucus hypersecretion is a trait of chronic obstructive pulmonary disease (COPD) associated with poorer outcomes. As it may be present before airway obstruction, its early treatment may have a preventive role. This narrative review of the literature presents the role of mucus dysfunction in COPD, its pathophysiology, and the rationale for the use of N-acetylcysteine (NAC). NAC can modify mucus rheology, improving clearance and reducing damage induced MUC5AC expression. It exerts a direct and indirect (glutathione replenishment) antioxidant mechanism; it interferes with inflammatory molecular pathways, including inhibition of nuclear factor-kB activation in epithelial airway cells and reduction in the expression of cytokine tumor necrosis factor α, interleukin (IL)-6, and IL-10. Some clinical experiences suggest that the adjunctive use of NAC may reduce symptoms and improve outcomes for patients with COPD. In conclusion, NAC may be a candidate drug for the early treatment of subjects at risk of COPD development.
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Affiliation(s)
- Federico Baraldi
- Section of Respiratory Medicine, Department of Translational Medicine, University of Ferrara
| | - Tommaso Bigoni
- Section of Respiratory Medicine, Department of Translational Medicine, University of Ferrara; Respiratory Unit, ULSS 8 Berica, Vicenza
| | | | | | - Giulia Scioscia
- Department of Medical and Surgical Sciences, University of Foggia; Respiratory Medicine, Policlinico of Foggia
| | | | - Alberto Papi
- Section of Respiratory Medicine, Department of Translational Medicine, University of Ferrara
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Liu B, Zhang W, Zeng X, Loza M, Park SJ, Nakai K. TF-EPI: an interpretable enhancer-promoter interaction detection method based on Transformer. Front Genet 2024; 15:1444459. [PMID: 39184348 PMCID: PMC11341371 DOI: 10.3389/fgene.2024.1444459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 07/24/2024] [Indexed: 08/27/2024] Open
Abstract
The detection of enhancer-promoter interactions (EPIs) is crucial for understanding gene expression regulation, disease mechanisms, and more. In this study, we developed TF-EPI, a deep learning model based on Transformer designed to detect these interactions solely from DNA sequences. The performance of TF-EPI surpassed that of other state-of-the-art methods on multiple benchmark datasets. Importantly, by utilizing the attention mechanism of the Transformer, we identified distinct cell type-specific motifs and sequences in enhancers and promoters, which were validated against databases such as JASPAR and UniBind, highlighting the potential of our method in discovering new biological insights. Moreover, our analysis of the transcription factors (TFs) corresponding to these motifs and short sequence pairs revealed the heterogeneity and commonality of gene regulatory mechanisms and demonstrated the ability to identify TFs relevant to the source information of the cell line. Finally, the introduction of transfer learning can mitigate the challenges posed by cell type-specific gene regulation, yielding enhanced accuracy in cross-cell line EPI detection. Overall, our work unveils important sequence information for the investigation of enhancer-promoter pairs based on the attention mechanism of the Transformer, providing an important milestone in the investigation of cis-regulatory grammar.
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Affiliation(s)
- Bowen Liu
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan
| | - Weihang Zhang
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan
| | - Xin Zeng
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan
| | - Martin Loza
- Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Sung-Joon Park
- Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Kenta Nakai
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan
- Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
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Jung MA, Lee JY, Kim YJ, Ji KY, Lee MH, Jung DH, Kim YH, Kim T. Dictamnus dasycarpus Turcz. attenuates airway inflammation and mucus hypersecretion by modulating the STAT6-STAT3/FOXA2 pathway. Biomed Pharmacother 2024; 173:116319. [PMID: 38422654 DOI: 10.1016/j.biopha.2024.116319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 02/16/2024] [Accepted: 02/19/2024] [Indexed: 03/02/2024] Open
Abstract
BACKGROUND Effects of Dictamnus dasycarpus Turcz. on allergic asthma and their underlying mechanisms remain unclarified. Thus, we investigated the effects of D. dasycarpus Turcz. water extract (DDW) on mucus hypersecretion in mice with ovalbumin (OVA)-induced asthma and human bronchial epithelial cells. METHODS BALB/c mice were used to establish an OVA-induced allergic asthma model. Mice were grouped into the OVA sensitization/challenge, 100 and 300 mg/kg DDW treatment, and dexamethasone groups. In mice, cell counts in bronchoalveolar lavage fluid (BALF), serum and BALF analyses, and histopathological lung tissue analyses were performed. Furthermore, we confirmed the basic mechanism in interleukin (IL)-4/IL-13-treated human bronchial epithelial cells through western blotting. RESULTS In OVA-induced asthma mice, DDW treatment reduced inflammatory cell number and airway hyperresponsiveness and ameliorated histological changes (immune cell infiltration, mucus secretion, and collagen deposition) in lung tissues and serum total immunoglobulin E levels. DDW treatment lowered BALF IL-4, IL-5, and IL-13 levels; reduced levels of inflammatory mediators, such as thymus- and activation-regulated chemokine, macrophage-derived chemokine, and interferon gamma-induced protein; decreased mucin 5AC (MUC5AC) production; decreased signal transducer and activator of transcription (STAT) 6 and STAT3 expression; and restored forkhead box protein A2 (FOXA2) expression. In IL-4/IL-13-treated human bronchial epithelial cells, DDW treatment inhibited MUC5AC production, suppressed STAT6 and STAT3 expression (related to mucus hypersecretion), and increased FOXA2 expression. CONCLUSIONS DDW treatment modulates MUC5AC expression and mucus hypersecretion by downregulating STAT6 and STAT3 expression and upregulating FOXA2 expression. These findings provide a novel approach to manage mucus hypersecretion in asthma using DDW.
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Affiliation(s)
- Myung-A Jung
- KM Convergence Research Division, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, the Republic of Korea
| | - Joo Young Lee
- KM Convergence Research Division, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, the Republic of Korea
| | - Yu Jin Kim
- KM Convergence Research Division, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, the Republic of Korea
| | - Kon-Young Ji
- KM Convergence Research Division, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, the Republic of Korea
| | - Mi Han Lee
- KM Convergence Research Division, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, the Republic of Korea
| | - Dong Ho Jung
- KM Convergence Research Division, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, the Republic of Korea
| | - Yun Hee Kim
- KM Convergence Research Division, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, the Republic of Korea
| | - Taesoo Kim
- KM Convergence Research Division, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, the Republic of Korea.
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Sponchiado M, Bonilla AL, Mata L, Jasso-Johnson K, Liao YSJ, Fagan A, Moncada V, Reznikov LR. Club cell CREB regulates the goblet cell transcriptional network and pro-mucin effects of IL-1B. Front Physiol 2023; 14:1323865. [PMID: 38173934 PMCID: PMC10761479 DOI: 10.3389/fphys.2023.1323865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 11/30/2023] [Indexed: 01/05/2024] Open
Abstract
Introduction: Club cells are precursors for mucus-producing goblet cells. Interleukin 1β (IL-1B) is an inflammatory mediator with pro-mucin activities that increases the number of mucus-producing goblet cells. IL-1B-mediated mucin production in alveolar adenocarcinoma cells requires activation of the cAMP response element-binding protein (CREB). Whether the pro-mucin activities of IL-1B require club cell CREB is unknown. Methods: We challenged male mice with conditional loss of club cell Creb1 and wild type littermates with intra-airway IL-1B or vehicle. Secondarily, we studied human "club cell-like" H322 cells. Results: IL-1B increased whole lung mRNA of secreted (Mucin 5ac, Mucin 5b) and tethered (Mucin 1, Mucin 4) mucins independent of genotype. However, loss of club cell Creb1 increased whole lung mRNA of member RAS oncogene family (Rab3D), decreased mRNA of the muscarinic receptor 3 (M3R) and prevented IL-1B mediated increases in purinergic receptor P2Y, (P2ry2) mRNA. IL-1B increased the density of goblet cells containing neutral mucins in wildtype mice but not in mice with loss of club cell Creb1. These findings suggested that club cell Creb1 regulated mucin secretion. Loss of club cell Creb1 also prevented IL-1B-mediated impairments in airway mechanics. Four days of pharmacologic CREB inhibition in H322 cells increased mRNA abundance of forkhead box A2 (FOXA2), a repressor of goblet cell expansion, and decreased mRNA expression of SAM pointed domain containing ETS transcription factor (SPDEF), a driver of goblet cell expansion. Chromatin immunoprecipitation demonstrated that CREB directly bound to the promoter region of FOXA2, but not to the promoter region of SPDEF. Treatment of H322 cells with IL-1B increased cAMP levels, providing a direct link between IL-1B and CREB signaling. Conclusion: Our findings suggest that club cell Creb1 regulates the pro-mucin properties of IL-1B through pathways likely involving FOXA2.
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Affiliation(s)
| | | | | | | | | | | | | | - Leah R. Reznikov
- Department of Physiological Sciences, University of Florida, Gainesville, FL, United States
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Haga Y, Sakamoto Y, Kajiya K, Kawai H, Oka M, Motoi N, Shirasawa M, Yotsukura M, Watanabe SI, Arai M, Zenkoh J, Shiraishi K, Seki M, Kanai A, Shiraishi Y, Yatabe Y, Matsubara D, Suzuki Y, Noguchi M, Kohno T, Suzuki A. Whole-genome sequencing reveals the molecular implications of the stepwise progression of lung adenocarcinoma. Nat Commun 2023; 14:8375. [PMID: 38102134 PMCID: PMC10724178 DOI: 10.1038/s41467-023-43732-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 11/17/2023] [Indexed: 12/17/2023] Open
Abstract
The mechanism underlying the development of tumors, particularly at early stages, still remains mostly elusive. Here, we report whole-genome long and short read sequencing analysis of 76 lung cancers, focusing on very early-stage lung adenocarcinomas such as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma. The obtained data is further integrated with bulk and spatial transcriptomic data and epigenomic data. These analyses reveal key events in lung carcinogenesis. Minimal somatic mutations in pivotal driver mutations and essential proliferative factors are the only detectable somatic mutations in the very early-stage of AIS. These initial events are followed by copy number changes and global DNA hypomethylation. Particularly, drastic changes are initiated at the later AIS stage, i.e., in Noguchi type B tumors, wherein cancer cells are exposed to the surrounding microenvironment. This study sheds light on the pathogenesis of lung adenocarcinoma from integrated pathological and molecular viewpoints.
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Affiliation(s)
- Yasuhiko Haga
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba, 277-8561, Japan
| | - Yoshitaka Sakamoto
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba, 277-8561, Japan
| | - Keiko Kajiya
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba, 277-8561, Japan
| | - Hitomi Kawai
- Department of Diagnostic Pathology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Miho Oka
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba, 277-8561, Japan
- Ono Pharmaceutical Co., Ltd., Ibaraki, Japan
| | - Noriko Motoi
- Department of Pathology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
- Department of Pathology, Saitama Cancer Center, 780 Komuro, Ina, Kita-Adachi-gun, Saitama, 362-0806, Japan
| | - Masayuki Shirasawa
- Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
- Division of Genome Biology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Masaya Yotsukura
- Department of Thoracic Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Shun-Ichi Watanabe
- Department of Thoracic Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Miyuki Arai
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba, 277-8561, Japan
| | - Junko Zenkoh
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba, 277-8561, Japan
| | - Kouya Shiraishi
- Division of Genome Biology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
- Department of Clinical Genomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Masahide Seki
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba, 277-8561, Japan
| | - Akinori Kanai
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba, 277-8561, Japan
| | - Yuichi Shiraishi
- Division of Genome Analysis Platform Development, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Yasushi Yatabe
- Department of Pathology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Daisuke Matsubara
- Department of Diagnostic Pathology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Yutaka Suzuki
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba, 277-8561, Japan.
| | - Masayuki Noguchi
- Department of Diagnostic Pathology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
- Clinical Cancer Research Division, Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura, Kanagawa, 247-8533, Japan
| | - Takashi Kohno
- Division of Genome Biology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
| | - Ayako Suzuki
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba, 277-8561, Japan.
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Das DN, Puthusseri B, Gopu V, Krishnan V, Bhagavath AK, Bolla S, Saini Y, Criner GJ, Marchetti N, Tang H, Konduru NV, Fan L, Shetty S. Caveolin-1-derived peptide attenuates cigarette smoke-induced airway and alveolar epithelial injury. Am J Physiol Lung Cell Mol Physiol 2023; 325:L689-L708. [PMID: 37642665 PMCID: PMC11178264 DOI: 10.1152/ajplung.00178.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/15/2023] [Accepted: 08/18/2023] [Indexed: 08/31/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a debilitating lung disease with no effective treatment that can reduce mortality or slow the disease progression. COPD is the third leading cause of global death and is characterized by airflow limitations due to chronic bronchitis and alveolar damage/emphysema. Chronic cigarette smoke (CS) exposure damages airway and alveolar epithelium and remains a major risk factor for the pathogenesis of COPD. We found that the expression of caveolin-1, a tumor suppressor protein; p53; and plasminogen activator inhibitor-1 (PAI-1), one of the downstream targets of p53, was markedly increased in airway epithelial cells (AECs) as well as in type II alveolar epithelial (AT2) cells from the lungs of patients with COPD or wild-type mice with CS-induced lung injury (CS-LI). Moreover, p53- and PAI-1-deficient mice resisted CS-LI. Furthermore, treatment of AECs, AT2 cells, or lung tissue slices from patients with COPD or mice with CS-LI with a seven amino acid caveolin-1 scaffolding domain peptide (CSP7) reduced mucus hypersecretion in AECs and improved AT2 cell viability. Notably, induction of PAI-1 expression via increased caveolin-1 and p53 contributed to mucous cell metaplasia and mucus hypersecretion in AECs, and reduced AT2 viability, due to increased senescence and apoptosis, which was abrogated by CSP7. In addition, treatment of wild-type mice having CS-LI with CSP7 by intraperitoneal injection or nebulization via airways attenuated mucus hypersecretion, alveolar injury, and significantly improved lung function. This study validates the potential therapeutic role of CSP7 for treating CS-LI and COPD. NEW & NOTEWORTHY Chronic cigarette smoke (CS) exposure remains a major risk factor for the pathogenesis of COPD, a debilitating disease with no effective treatment. Increased caveolin-1 mediated induction of p53 and downstream plasminogen activator inhibitor-1 (PAI-1) expression contributes to CS-induced airway mucus hypersecretion and alveolar wall damage. This is reversed by caveolin-1 scaffolding domain peptide (CSP7) in preclinical models, suggesting the therapeutic potential of CSP7 for treating CS-induced lung injury (CS-LI) and COPD.
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Affiliation(s)
- Durgesh Nandini Das
- Department of Medicine, Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas, United States
| | - Bijesh Puthusseri
- Department of Medicine, Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas, United States
| | - Venkadesaperumal Gopu
- Department of Medicine, Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas, United States
| | - Venugopal Krishnan
- Department of Medicine, Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas, United States
| | - Ashoka Kumar Bhagavath
- Department of Medicine, Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas, United States
| | - Sudhir Bolla
- Temple University Hospital, Philadelphia, Pennsylvania, United States
| | - Yogesh Saini
- School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, United States
| | - Gerald J Criner
- Temple University Hospital, Philadelphia, Pennsylvania, United States
| | | | - Hua Tang
- Department of Medicine, Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas, United States
| | - Nagarjun V Konduru
- Department of Medicine, Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas, United States
| | - Liang Fan
- Department of Medicine, Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas, United States
| | - Sreerama Shetty
- Department of Medicine, Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, Texas, United States
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Rodenburg LW, Metzemaekers M, van der Windt IS, Smits SMA, den Hertog-Oosterhoff LA, Kruisselbrink E, Brunsveld JE, Michel S, de Winter-de Groot KM, van der Ent CK, Stadhouders R, Beekman JM, Amatngalim GD. Exploring intrinsic variability between cultured nasal and bronchial epithelia in cystic fibrosis. Sci Rep 2023; 13:18573. [PMID: 37903789 PMCID: PMC10616285 DOI: 10.1038/s41598-023-45201-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 10/17/2023] [Indexed: 11/01/2023] Open
Abstract
The nasal and bronchial epithelium are unified parts of the respiratory tract that are affected in the monogenic disorder cystic fibrosis (CF). Recent studies have uncovered that nasal and bronchial tissues exhibit intrinsic variability, including differences in mucociliary cell composition and expression of unique transcriptional regulatory proteins which relate to germ layer origin. In the present study, we explored whether intrinsic differences between nasal and bronchial epithelial cells persist in cell cultures and affect epithelial cell functioning in CF. Comparison of air-liquid interface (ALI) differentiated epithelial cells from subjects with CF revealed distinct mucociliary differentiation states of nasal and bronchial cultures. Moreover, using RNA sequencing we identified cell type-specific signature transcription factors in differentiated nasal and bronchial epithelial cells, some of which were already poised for expression in basal progenitor cells as evidenced by ATAC sequencing. Analysis of differentiated nasal and bronchial epithelial 3D organoids revealed distinct capacities for fluid secretion, which was linked to differences in ciliated cell differentiation. In conclusion, we show that unique phenotypical and functional features of nasal and bronchial epithelial cells persist in cell culture models, which can be further used to investigate the effects of tissue-specific features on upper and lower respiratory disease development in CF.
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Affiliation(s)
- Lisa W Rodenburg
- Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Member of ERN-LUNG, 3584 EA, Utrecht, The Netherlands.
- Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht University, 3584 CT, Utrecht, The Netherlands.
| | - Mieke Metzemaekers
- Department of Pulmonary Medicine, Erasmus University Medical Center, 3015 CE, Rotterdam, The Netherlands
- Department of Cell Biology, Erasmus University Medical Center, 3015 CE, Rotterdam, The Netherlands
| | - Isabelle S van der Windt
- Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Member of ERN-LUNG, 3584 EA, Utrecht, The Netherlands
- Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht University, 3584 CT, Utrecht, The Netherlands
| | - Shannon M A Smits
- Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Member of ERN-LUNG, 3584 EA, Utrecht, The Netherlands
- Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht University, 3584 CT, Utrecht, The Netherlands
| | - Loes A den Hertog-Oosterhoff
- Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Member of ERN-LUNG, 3584 EA, Utrecht, The Netherlands
- Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht University, 3584 CT, Utrecht, The Netherlands
| | - Evelien Kruisselbrink
- Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Member of ERN-LUNG, 3584 EA, Utrecht, The Netherlands
- Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht University, 3584 CT, Utrecht, The Netherlands
| | - Jesse E Brunsveld
- Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Member of ERN-LUNG, 3584 EA, Utrecht, The Netherlands
- Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht University, 3584 CT, Utrecht, The Netherlands
| | - Sabine Michel
- Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Member of ERN-LUNG, 3584 EA, Utrecht, The Netherlands
| | - Karin M de Winter-de Groot
- Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Member of ERN-LUNG, 3584 EA, Utrecht, The Netherlands
| | - Cornelis K van der Ent
- Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Member of ERN-LUNG, 3584 EA, Utrecht, The Netherlands
| | - Ralph Stadhouders
- Department of Pulmonary Medicine, Erasmus University Medical Center, 3015 CE, Rotterdam, The Netherlands
- Department of Cell Biology, Erasmus University Medical Center, 3015 CE, Rotterdam, The Netherlands
| | - Jeffrey M Beekman
- Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Member of ERN-LUNG, 3584 EA, Utrecht, The Netherlands
- Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht University, 3584 CT, Utrecht, The Netherlands
- Centre for Living Technologies, Alliance TU/e, WUR, UU, UMC Utrecht, 3584 CB, Utrecht, The Netherlands
| | - Gimano D Amatngalim
- Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Member of ERN-LUNG, 3584 EA, Utrecht, The Netherlands
- Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht University, 3584 CT, Utrecht, The Netherlands
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11
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Miura A, Sarmah H, Tanaka J, Hwang Y, Sawada A, Shimamura Y, Otoshi T, Kondo Y, Fang Y, Shimizu D, Ninish Z, Suer JL, Dubois NC, Davis J, Toyooka S, Wu J, Que J, Hawkins FJ, Lin CS, Mori M. Conditional blastocyst complementation of a defective Foxa2 lineage efficiently promotes the generation of the whole lung. eLife 2023; 12:e86105. [PMID: 37861292 PMCID: PMC10642968 DOI: 10.7554/elife.86105] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 10/19/2023] [Indexed: 10/21/2023] Open
Abstract
Millions suffer from incurable lung diseases, and the donor lung shortage hampers organ transplants. Generating the whole organ in conjunction with the thymus is a significant milestone for organ transplantation because the thymus is the central organ to educate immune cells. Using lineage-tracing mice and human pluripotent stem cell (PSC)-derived lung-directed differentiation, we revealed that gastrulating Foxa2 lineage contributed to both lung mesenchyme and epithelium formation. Interestingly, Foxa2 lineage-derived cells in the lung mesenchyme progressively increased and occupied more than half of the mesenchyme niche, including endothelial cells, during lung development. Foxa2 promoter-driven, conditional Fgfr2 gene depletion caused the lung and thymus agenesis phenotype in mice. Wild-type donor mouse PSCs injected into their blastocysts rescued this phenotype by complementing the Fgfr2-defective niche in the lung epithelium and mesenchyme and thymic epithelium. Donor cell is shown to replace the entire lung epithelial and robust mesenchymal niche during lung development, efficiently complementing the nearly entire lung niche. Importantly, those mice survived until adulthood with normal lung function. These results suggest that our Foxa2 lineage-based model is unique for the progressive mobilization of donor cells into both epithelial and mesenchymal lung niches and thymus generation, which can provide critical insights into studying lung transplantation post-transplantation shortly.
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Affiliation(s)
- Akihiro Miura
- Columbia Center for Human Development and Division of Pulmonary, Allergy, Critical Care, Department of Medicine, Columbia University Medical CenterNew YorkUnited States
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
| | - Hemanta Sarmah
- Columbia Center for Human Development and Division of Pulmonary, Allergy, Critical Care, Department of Medicine, Columbia University Medical CenterNew YorkUnited States
| | - Junichi Tanaka
- Columbia Center for Human Development and Division of Pulmonary, Allergy, Critical Care, Department of Medicine, Columbia University Medical CenterNew YorkUnited States
| | - Youngmin Hwang
- Columbia Center for Human Development and Division of Pulmonary, Allergy, Critical Care, Department of Medicine, Columbia University Medical CenterNew YorkUnited States
| | - Anri Sawada
- Columbia Center for Human Development and Division of Pulmonary, Allergy, Critical Care, Department of Medicine, Columbia University Medical CenterNew YorkUnited States
| | - Yuko Shimamura
- Columbia Center for Human Development and Division of Pulmonary, Allergy, Critical Care, Department of Medicine, Columbia University Medical CenterNew YorkUnited States
| | - Takehiro Otoshi
- Columbia Center for Human Development and Division of Pulmonary, Allergy, Critical Care, Department of Medicine, Columbia University Medical CenterNew YorkUnited States
| | - Yuri Kondo
- Columbia Center for Human Development and Division of Pulmonary, Allergy, Critical Care, Department of Medicine, Columbia University Medical CenterNew YorkUnited States
| | - Yinshan Fang
- Columbia Center for Human Development and Division of Pulmonary, Allergy, Critical Care, Department of Medicine, Columbia University Medical CenterNew YorkUnited States
| | - Dai Shimizu
- Columbia Center for Human Development and Division of Pulmonary, Allergy, Critical Care, Department of Medicine, Columbia University Medical CenterNew YorkUnited States
| | - Zurab Ninish
- Columbia Center for Human Development and Division of Pulmonary, Allergy, Critical Care, Department of Medicine, Columbia University Medical CenterNew YorkUnited States
| | - Jake Le Suer
- The Pulmonary Center and Department of Medicine, Boston University School of MedicineBostonUnited States
- Center for Regenerative Medicine, Boston University and Boston Medical CenterBostonUnited States
| | - Nicole C Dubois
- Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Jennifer Davis
- Department of Pathology, University of WashingtonSeattleUnited States
| | - Shinichi Toyooka
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
| | - Jun Wu
- Department of Molecular Biology, University of Texas Southwestern Medical CenterDallasUnited States
| | - Jianwen Que
- Columbia Center for Human Development and Division of Pulmonary, Allergy, Critical Care, Department of Medicine, Columbia University Medical CenterNew YorkUnited States
| | - Finn J Hawkins
- The Pulmonary Center and Department of Medicine, Boston University School of MedicineBostonUnited States
- Center for Regenerative Medicine, Boston University and Boston Medical CenterBostonUnited States
| | - Chyuan-Sheng Lin
- Bernard and Shirlee Brown Glaucoma Laboratory, Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University Irving Medical CenterNew YorkUnited States
| | - Munemasa Mori
- Columbia Center for Human Development and Division of Pulmonary, Allergy, Critical Care, Department of Medicine, Columbia University Medical CenterNew YorkUnited States
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12
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Hou L, Xiong X, Park Y, Boix C, James B, Sun N, He L, Patel A, Zhang Z, Molinie B, Van Wittenberghe N, Steelman S, Nusbaum C, Aguet F, Ardlie KG, Kellis M. Multitissue H3K27ac profiling of GTEx samples links epigenomic variation to disease. Nat Genet 2023; 55:1665-1676. [PMID: 37770633 PMCID: PMC10562256 DOI: 10.1038/s41588-023-01509-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 08/22/2023] [Indexed: 09/30/2023]
Abstract
Genetic variants associated with complex traits are primarily noncoding, and their effects on gene-regulatory activity remain largely uncharacterized. To address this, we profile epigenomic variation of histone mark H3K27ac across 387 brain, heart, muscle and lung samples from Genotype-Tissue Expression (GTEx). We annotate 282 k active regulatory elements (AREs) with tissue-specific activity patterns. We identify 2,436 sex-biased AREs and 5,397 genetically influenced AREs associated with 130 k genetic variants (haQTLs) across tissues. We integrate genetic and epigenomic variation to provide mechanistic insights for disease-associated loci from 55 genome-wide association studies (GWAS), by revealing candidate tissues of action, driver SNPs and impacted AREs. Lastly, we build ARE-gene linking scores based on genetics (gLink scores) and demonstrate their unique ability to prioritize SNP-ARE-gene circuits. Overall, our epigenomic datasets, computational integration and mechanistic predictions provide valuable resources and important insights for understanding the molecular basis of human diseases/traits such as schizophrenia.
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Affiliation(s)
- Lei Hou
- Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA, USA
- The Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Xushen Xiong
- Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA, USA
- The Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Liangzhu Laboratory, Zhejiang University, Hangzhou, China
| | - Yongjin Park
- Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA, USA
- The Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Carles Boix
- Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA, USA
- The Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Benjamin James
- Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA, USA
- The Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Na Sun
- Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA, USA
- The Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Liang He
- Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA, USA
- The Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Aman Patel
- Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA, USA
- The Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Zhizhuo Zhang
- Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA, USA
- The Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Benoit Molinie
- The Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | | | - Scott Steelman
- The Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Chad Nusbaum
- The Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - François Aguet
- The Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | | | - Manolis Kellis
- Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA, USA.
- The Broad Institute of Harvard and MIT, Cambridge, MA, USA.
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13
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Cumplido-Laso G, Benitez DA, Mulero-Navarro S, Carvajal-Gonzalez JM. Transcriptional Regulation of Airway Epithelial Cell Differentiation: Insights into the Notch Pathway and Beyond. Int J Mol Sci 2023; 24:14789. [PMID: 37834236 PMCID: PMC10573127 DOI: 10.3390/ijms241914789] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 09/15/2023] [Accepted: 09/25/2023] [Indexed: 10/15/2023] Open
Abstract
The airway epithelium is a critical component of the respiratory system, serving as a barrier against inhaled pathogens and toxins. It is composed of various cell types, each with specific functions essential to proper airway function. Chronic respiratory diseases can disrupt the cellular composition of the airway epithelium, leading to a decrease in multiciliated cells (MCCs) and an increase in secretory cells (SCs). Basal cells (BCs) have been identified as the primary stem cells in the airway epithelium, capable of self-renewal and differentiation into MCCs and SCs. This review emphasizes the role of transcription factors in the differentiation process from BCs to MCCs and SCs. Recent advancements in single-cell RNA sequencing (scRNAseq) techniques have provided insights into the cellular composition of the airway epithelium, revealing specialized and rare cell types, including neuroendocrine cells, tuft cells, and ionocytes. Understanding the cellular composition and differentiation processes within the airway epithelium is crucial for developing targeted therapies for respiratory diseases. Additionally, the maintenance of BC populations and the involvement of Notch signaling in BC self-renewal and differentiation are discussed. Further research in these areas could provide valuable insights into the mechanisms underlying airway epithelial homeostasis and disease pathogenesis.
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Affiliation(s)
- Guadalupe Cumplido-Laso
- Departamento de Bioquímica, Biología Molecular y Genética, Facultad de Ciencias, Universidad de Extremadura, 06071 Badajoz, Spain; (D.A.B.); (S.M.-N.)
| | | | | | - Jose Maria Carvajal-Gonzalez
- Departamento de Bioquímica, Biología Molecular y Genética, Facultad de Ciencias, Universidad de Extremadura, 06071 Badajoz, Spain; (D.A.B.); (S.M.-N.)
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14
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Clarke DM, Curtis KL, Wendt RA, Stapley BM, Clark ET, Beckett N, Campbell KM, Arroyo JA, Reynolds PR. Decreased Expression of Pulmonary Homeobox NKX2.1 and Surfactant Protein C in Developing Lungs That Over-Express Receptors for Advanced Glycation End-Products (RAGE). J Dev Biol 2023; 11:33. [PMID: 37489334 PMCID: PMC10366714 DOI: 10.3390/jdb11030033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 07/03/2023] [Accepted: 07/06/2023] [Indexed: 07/26/2023] Open
Abstract
Receptors for advanced glycation end-products (RAGE) are multi-ligand cell surface receptors of the immunoglobin superfamily prominently expressed by lung epithelium. Previous experiments demonstrated that over-expression of RAGE by murine alveolar epithelium throughout embryonic development causes neonatal lethality coincident with significant lung hypoplasia. In the current study, we evaluated the expression of NKX2.1 (also referred to as TTF-1), a homeodomain-containing transcription factor critical for branching morphogenesis, in mice that differentially expressed RAGE. We also contextualized NKX2.1 expression with the abundance of FoxA2, a winged double helix DNA binding protein that influences respiratory epithelial cell differentiation and surfactant protein expression. Conditional RAGE over-expression was induced in mouse lung throughout gestation (embryonic day E0-18.5), as well as during the critical saccular period of development (E15.5-18.5), and analyses were conducted at E18.5. Histology revealed markedly less lung parenchyma beginning in the canalicular stage of lung development and continuing throughout the saccular period. We discovered consistently decreased expression of both NKX2.1 and FoxA2 in lungs from transgenic (TG) mice compared to littermate controls. We also observed diminished surfactant protein C in TG mice, suggesting possible hindered differentiation and/or proliferation of alveolar epithelial cells under the genetic control of these two critical transcription factors. These results demonstrate that RAGE must be specifically regulated during lung formation. Perturbation of epithelial cell differentiation culminating in respiratory distress and perinatal lethality may coincide with elevated RAGE expression in the lung parenchyma.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Paul R. Reynolds
- Lung and Placenta Laboratory, Department of Cell Biology and Physiology, Brigham Young University, Provo, UT 84602, USA
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15
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Shah BK, Singh B, Wang Y, Xie S, Wang C. Mucus Hypersecretion in Chronic Obstructive Pulmonary Disease and Its Treatment. Mediators Inflamm 2023; 2023:8840594. [PMID: 37457746 PMCID: PMC10344637 DOI: 10.1155/2023/8840594] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 05/29/2023] [Accepted: 06/23/2023] [Indexed: 07/18/2023] Open
Abstract
Most patients diagnosed with chronic obstructive pulmonary disease (COPD) present with hallmark features of airway mucus hypersecretion, including cough and expectoration. Airway mucus function as a native immune system of the lung that severs to trap particulate matter and pathogens and allows them to clear from the lung via cough and ciliary transport. Chronic mucus hypersecretion (CMH) is the main factor contributing to the increased risk of morbidity and mortality in specific subsets of COPD patients. It is, therefore, primarily important to develop medications that suppress mucus hypersecretions in these patients. Although there have been some advances in COPD treatment, more work remains to be done to better understand the mechanism underlying airway mucus hypersecretion and seek more effective treatments. This review article discusses the structure and significance of mucus in the lungs focusing on gel-forming mucins and the impacts of CMH in the lungs. Furthermore, we summarize the article with pharmacological and nonpharmacological treatments as well as novel and interventional procedures to control CMH in COPD patients.
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Affiliation(s)
- Binay Kumar Shah
- Department of Respiratory Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
- Tongji University School of Medicine, Shanghai 200092, China
| | - Bivek Singh
- Tongji University School of Medicine, Shanghai 200092, China
| | - Yukun Wang
- Tongji University School of Medicine, Shanghai 200092, China
| | - Shuanshuan Xie
- Department of Respiratory Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Changhui Wang
- Department of Respiratory Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
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16
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Hsieh A, Assadinia N, Hackett TL. Airway remodeling heterogeneity in asthma and its relationship to disease outcomes. Front Physiol 2023; 14:1113100. [PMID: 36744026 PMCID: PMC9892557 DOI: 10.3389/fphys.2023.1113100] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 01/05/2023] [Indexed: 01/20/2023] Open
Abstract
Asthma affects an estimated 262 million people worldwide and caused over 461,000 deaths in 2019. The disease is characterized by chronic airway inflammation, reversible bronchoconstriction, and airway remodeling. Longitudinal studies have shown that current treatments for asthma (inhaled bronchodilators and corticosteroids) can reduce the frequency of exacerbations, but do not modify disease outcomes over time. Further, longitudinal studies in children to adulthood have shown that these treatments do not improve asthma severity or fixed airflow obstruction over time. In asthma, fixed airflow obstruction is caused by remodeling of the airway wall, but such airway remodeling also significantly contributes to airway closure during bronchoconstriction in acute asthmatic episodes. The goal of the current review is to understand what is known about the heterogeneity of airway remodeling in asthma and how this contributes to the disease process. We provide an overview of the existing knowledge on airway remodeling features observed in asthma, including loss of epithelial integrity, mucous cell metaplasia, extracellular matrix remodeling in both the airways and vessels, angiogenesis, and increased smooth muscle mass. While such studies have provided extensive knowledge on different aspects of airway remodeling, they have relied on biopsy sampling or pathological assessment of lungs from fatal asthma patients, which have limitations for understanding airway heterogeneity and the entire asthma syndrome. To further understand the heterogeneity of airway remodeling in asthma, we highlight the potential of in vivo imaging tools such as computed tomography and magnetic resonance imaging. Such volumetric imaging tools provide the opportunity to assess the heterogeneity of airway remodeling within the whole lung and have led to the novel identification of heterogenous gas trapping and mucus plugging as important predictors of patient outcomes. Lastly, we summarize the current knowledge of modification of airway remodeling with available asthma therapeutics to highlight the need for future studies that use in vivo imaging tools to assess airway remodeling outcomes.
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Affiliation(s)
- Aileen Hsieh
- Centre for Heart Lung Innovation, St. Paul’s Hospital, Vancouver, BC, Canada,Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada
| | - Najmeh Assadinia
- Centre for Heart Lung Innovation, St. Paul’s Hospital, Vancouver, BC, Canada,Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada
| | - Tillie-Louise Hackett
- Centre for Heart Lung Innovation, St. Paul’s Hospital, Vancouver, BC, Canada,Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada,*Correspondence: Tillie-Louise Hackett,
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17
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Yánez DC, Lau CI, Papaioannou E, Chawda MM, Rowell J, Ross S, Furmanski A, Crompton T. The Pioneer Transcription Factor Foxa2 Modulates T Helper Differentiation to Reduce Mouse Allergic Airway Disease. Front Immunol 2022; 13:890781. [PMID: 36003391 PMCID: PMC9393229 DOI: 10.3389/fimmu.2022.890781] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Accepted: 05/18/2022] [Indexed: 12/17/2022] Open
Abstract
Foxa2, a member of the Forkhead box (Fox) family of transcription factors, plays an important role in the regulation of lung function and lung tissue homeostasis. FOXA2 expression is reduced in the lung and airways epithelium of asthmatic patients and in mice absence of Foxa2 from the lung epithelium contributes to airway inflammation and goblet cell hyperplasia. Here we demonstrate a novel role for Foxa2 in the regulation of T helper differentiation and investigate its impact on lung inflammation. Conditional deletion of Foxa2 from T-cells led to increased Th2 cytokine secretion and differentiation, but decreased Th1 differentiation and IFN-γ expression in vitro. Induction of mouse allergic airway inflammation resulted in more severe disease in the conditional Foxa2 knockout than in control mice, with increased cellular infiltration to the lung, characterized by the recruitment of eosinophils and basophils, increased mucus production and increased production of Th2 cytokines and serum IgE. Thus, these experiments suggest that Foxa2 expression in T-cells is required to protect against the Th2 inflammatory response in allergic airway inflammation and that Foxa2 is important in T-cells to maintain the balance of effector cell differentiation and function in the lung.
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Affiliation(s)
- Diana C Yánez
- UCL Great Ormond Street Institute of Child Health, London, United Kingdom
- School of Medicine, Universidad San Francisco de Quito, Quito, Ecuador
| | - Ching-In Lau
- UCL Great Ormond Street Institute of Child Health, London, United Kingdom
| | | | - Mira M Chawda
- UCL Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Jasmine Rowell
- UCL Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Susan Ross
- UCL Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Anna Furmanski
- UCL Great Ormond Street Institute of Child Health, London, United Kingdom
- School of Life Sciences, University of Bedfordshire, Luton, United Kingdom
| | - Tessa Crompton
- UCL Great Ormond Street Institute of Child Health, London, United Kingdom
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18
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Lin Y, Wang D, Zeng Y. A Maverick Review of Common Stem/Progenitor Markers in Lung Development. Stem Cell Rev Rep 2022; 18:2629-2645. [DOI: 10.1007/s12015-022-10422-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2022] [Indexed: 10/16/2022]
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19
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Ueshima S, Fang J. Histone H3K9 methyltransferase SETDB1 augments invadopodia formation to promote tumor metastasis. Oncogene 2022; 41:3370-3380. [PMID: 35546351 PMCID: PMC9801494 DOI: 10.1038/s41388-022-02345-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 04/27/2022] [Accepted: 05/03/2022] [Indexed: 01/04/2023]
Abstract
Non-small cell lung cancer (NSCLC) is one of leading causes of cancer-related mortality worldwide, which harbors various accumulated genetic and epigenetic abnormalities. Histone methyltransferase SETDB1 is a pivotal epigenetic regulator whose focal amplification and upregulation are commonly detected in NSCLC. However, molecular mechanisms underlying the pro-oncogenic function of SETDB1 remain poorly characterized. Here, we demonstrate that SETDB1 augments the migration and invasion capabilities of NSCLC cells by reinforcing invadopodia formation and mediated ECM degradation. At the molecular level, SETDB1 suppresses the expression of FOXA2, a crucial tumor and metastasis suppressor via coordinated epigenetic mechanisms - SETDB1 not only catalyzes histone H3K9 methylation on FOXA2 genomic locus, but also recruits DNMT3A to regulate DNA methylation on CpG island. Consequently, depletion of Setdb1 in murine lung adenocarcinoma cells completely abolished their full and spontaneous metastatic capabilities in mouse xenograft models. These findings together establish the pro-metastasis activity of SETDB1 in NSCLC and elucidate the underlying cellular and molecular mechanisms.
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Affiliation(s)
- Shuhei Ueshima
- Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Jia Fang
- Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
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20
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Bee Venom Prevents Mucin 5AC Production through Inhibition of AKT and SPDEF Activation in Airway Epithelia Cells. Toxins (Basel) 2021; 13:toxins13110773. [PMID: 34822557 PMCID: PMC8619940 DOI: 10.3390/toxins13110773] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 10/18/2021] [Accepted: 10/28/2021] [Indexed: 11/16/2022] Open
Abstract
IL-13 induces mucus metaplasia, which causes airway obstruction in asthma. Bee venom (BV) and its components have shown anti-inflammatory effects in allergic diseases such as atopic dermatitis and asthma. In this study, we investigated the effect of BV on IL-13-induced mucus metaplasia through activation of the signal transducer and activator of transcription (STAT6), and regulation of SAM-pointed domain containing Ets-like factor (SPDEF) and forkhead box A2 (FOXA2) in the airway epithelia cell line A549. In A549 cells, BV (1.0 µg/mL) inhibited IL-13 (10 ng/mL)-induced AKT phosphorylation, increase in SPDEF protein expression, and decrease in FOXA2 protein expression—but not STAT6 phosphorylation. BV also prevented the IL-13-induced increase in mucin 5AC (MUC5AC) mRNA and protein expression. Moreover, we observed that inhibition of phosphoinositide 3 kinase (PI3K)/AKT using LY294002 (50 µM) could reverse the alterations in FOXA2 and MUC5AC expression -by IL-13 and BV. However, LY294002 did not affect IL-13- and BV-induced changes in SPDEF expression. These findings indicate that BV inhibits MUC5AC production through the regulation of SPDEF and FOXA2. The inhibition of MUC5AC production through FOXA2 is mediated via the suppression of PI3K/AKT activation by BV. BV may be helpful in the prevention of mucus metaplasia in asthma.
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21
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Johansson K, Woodruff PG, Ansel KM. Regulation of airway immunity by epithelial miRNAs. Immunol Rev 2021; 304:141-153. [PMID: 34549450 PMCID: PMC9135676 DOI: 10.1111/imr.13028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/17/2021] [Accepted: 08/20/2021] [Indexed: 02/07/2023]
Abstract
The airway epithelium is essential to protect the host from inhaled pathogens and particles. It maintains immune homeostasis and mediates tissue repair after injury. Inflammatory diseases of the airways are associated with failure of epithelial functions, including loss of barrier integrity that results in increased tissue permeability and immune activation; excessive mucus secretion and impaired mucociliary clearance that leads to airflow obstruction and microbial overgrowth; and dysregulation of cellular signals that promotes inflammation and alters tissue structure and airway reactivity. MicroRNAs play crucial roles in mounting appropriate cellular responses to environmental stimuli and preventing disease, using a common machinery and mechanism to regulate gene expression in epithelial cells, immune cells of hematopoietic origin, and other cellular components of the airways. Respiratory diseases are accompanied by dramatic changes in epithelial miRNA expression that drive persistent immune dysregulation. In this review, we discuss responses of the epithelium that promote airway immunopathology, with a focus on miRNAs that contribute to the breakdown of essential epithelial functions. We emphasize the emerging role of miRNAs in regulation of epithelial responses in respiratory health and their value as diagnostic and therapeutic targets.
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Affiliation(s)
- Kristina Johansson
- Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
- Sandler Asthma Basic Research Center, University of California, San Francisco, California, USA
- Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy, University of California, San Francisco, California, USA
- Department of Microbiology and Immunology, University of California, San Francisco, California, USA
| | - Prescott G. Woodruff
- Sandler Asthma Basic Research Center, University of California, San Francisco, California, USA
- Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy, University of California, San Francisco, California, USA
- Cardiovascular Research Institute, University of California, San Francisco, California, USA
| | - K. Mark Ansel
- Sandler Asthma Basic Research Center, University of California, San Francisco, California, USA
- Department of Microbiology and Immunology, University of California, San Francisco, California, USA
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22
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Xu X, Li J, Zhang Y, Zhang L. Arachidonic Acid 15-Lipoxygenase: Effects of Its Expression, Metabolites, and Genetic and Epigenetic Variations on Airway Inflammation. ALLERGY, ASTHMA & IMMUNOLOGY RESEARCH 2021; 13:684-696. [PMID: 34486255 PMCID: PMC8419644 DOI: 10.4168/aair.2021.13.5.684] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/18/2021] [Accepted: 05/26/2021] [Indexed: 01/21/2023]
Abstract
Arachidonic acid 15-lipoxygenase (ALOX15) is an enzyme that can oxidize polyunsaturated fatty acids. ALOX15 is strongly expressed in airway epithelial cells, where it catalyzes the conversion of arachidonic acid to 15-hydroxyeicosatetraenoic acid (15-HETE) involved in various airway inflammatory diseases. Interleukin (IL)-4 and IL-13 induce ALOX15 expression by activating Jak2 and Tyk2 kinases as well as signal transducers and activators of transcription (STATs) 1/3/5/6. ALOX15 up-regulation and subsequent association with phosphatidylethanolamine-binding protein 1 (PEBP1) activate the mitogen-activated extracellular signal-regulated kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway, thus inducing eosinophil-mediated airway inflammation. In addition, ALOX15 plays a significant role in promoting the migration of immune cells, such as immature dendritic cells, activated T cells, and mast cells, and airway remodeling, including goblet cell differentiation. Genome-wide association studies have revealed multiple ALOX15 variants and their significant correlation with the risk of developing airway diseases. The epigenetic modifications of the ALOX15 gene, such as DNA methylation and histone modifications, have been shown to closely relate with airway inflammation. This review summarizes the role of ALOX15 in different phenotypes of asthma, chronic obstructive pulmonary disease, chronic rhinosinusitis, aspirin-exacerbated respiratory disease, and nasal polyps, suggesting new treatment strategies for these airway inflammatory diseases with complex etiology and poor treatment response.
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Affiliation(s)
- Xu Xu
- Department of Otolaryngology Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China
| | - Jingyun Li
- Department of Otolaryngology Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, China
| | - Yuan Zhang
- Department of Otolaryngology Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, China.,Department of Allergy, Beijing TongRen Hospital, Capital Medical University, Beijing, China.
| | - Luo Zhang
- Department of Otolaryngology Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, China.,Department of Allergy, Beijing TongRen Hospital, Capital Medical University, Beijing, China.
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23
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Paranjapye A, NandyMazumdar M, Browne JA, Leir SH, Harris A. Krüppel-like factor 5 regulates wound repair and the innate immune response in human airway epithelial cells. J Biol Chem 2021; 297:100932. [PMID: 34217701 PMCID: PMC8353497 DOI: 10.1016/j.jbc.2021.100932] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 06/17/2021] [Accepted: 06/29/2021] [Indexed: 12/23/2022] Open
Abstract
A complex network of transcription factors regulates genes involved in establishing and maintaining key biological properties of the human airway epithelium. However, detailed knowledge of the contributing factors is incomplete. Here we characterize the role of Krüppel-like factor 5 (KLF5), in controlling essential pathways of epithelial cell identity and function in the human lung. RNA-seq following siRNA-mediated depletion of KLF5 in the Calu-3 lung epithelial cell line identified significant enrichment of genes encoding chemokines and cytokines involved in the proinflammatory response and also components of the junctional complexes mediating cell adhesion. To determine direct gene targets of KLF5, we defined the cistrome of KLF5 using ChIP-seq in both Calu-3 and 16HBE14o- lung epithelial cell lines. Occupancy site concordance analysis revealed that KLF5 colocalized with the active histone modification H3K27ac and also with binding sites for the transcription factor CCAAT enhancer-binding protein beta (C/EBPβ). Depletion of KLF5 increased both the expression and secretion of cytokines including IL-1β, a response that was enhanced following exposure to Pseudomonas aeruginosa lipopolysaccharide. Calu-3 cells exhibited faster rates of repair after KLF5 depletion compared with negative controls in wound scratch assays. Similarly, CRISPR-mediated KLF5-null 16HBE14o- cells also showed enhanced wound closure. These data reveal a pivotal role for KLF5 in coordinating epithelial functions relevant to human lung disease.
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Affiliation(s)
- Alekh Paranjapye
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, USA
| | - Monali NandyMazumdar
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, USA
| | - James A Browne
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, USA
| | - Shih-Hsing Leir
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, USA
| | - Ann Harris
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
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24
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Morin CD, Déziel E, Gauthier J, Levesque RC, Lau GW. An Organ System-Based Synopsis of Pseudomonas aeruginosa Virulence. Virulence 2021; 12:1469-1507. [PMID: 34180343 PMCID: PMC8237970 DOI: 10.1080/21505594.2021.1926408] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Driven in part by its metabolic versatility, high intrinsic antibiotic resistance, and a large repertoire of virulence factors, Pseudomonas aeruginosa is expertly adapted to thrive in a wide variety of environments, and in the process, making it a notorious opportunistic pathogen. Apart from the extensively studied chronic infection in the lungs of people with cystic fibrosis (CF), P. aeruginosa also causes multiple serious infections encompassing essentially all organs of the human body, among others, lung infection in patients with chronic obstructive pulmonary disease, primary ciliary dyskinesia and ventilator-associated pneumonia; bacteremia and sepsis; soft tissue infection in burns, open wounds and postsurgery patients; urinary tract infection; diabetic foot ulcers; chronic suppurative otitis media and otitis externa; and keratitis associated with extended contact lens use. Although well characterized in the context of CF, pathogenic processes mediated by various P. aeruginosa virulence factors in other organ systems remain poorly understood. In this review, we use an organ system-based approach to provide a synopsis of disease mechanisms exerted by P. aeruginosa virulence determinants that contribute to its success as a versatile pathogen.
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Affiliation(s)
- Charles D Morin
- Centre Armand-Frappier Santé Biotechnologie, Institut National De La Recherche Scientifique (INRS), Laval, Quebec, Canada
| | - Eric Déziel
- Centre Armand-Frappier Santé Biotechnologie, Institut National De La Recherche Scientifique (INRS), Laval, Quebec, Canada
| | - Jeff Gauthier
- Département De Microbiologie-infectiologie Et Immunologie, Institut De Biologie Intégrative Et Des Systèmes (IBIS), Université Laval, Québec City, Quebec, Canada
| | - Roger C Levesque
- Département De Microbiologie-infectiologie Et Immunologie, Institut De Biologie Intégrative Et Des Systèmes (IBIS), Université Laval, Québec City, Quebec, Canada
| | - Gee W Lau
- Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL, US
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25
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Chenery AL, Rosini S, Parkinson JE, Ajendra J, Herrera JA, Lawless C, Chan BHK, Loke P, MacDonald AS, Kadler KE, Sutherland TE, Allen JE. IL-13 deficiency exacerbates lung damage and impairs epithelial-derived type 2 molecules during nematode infection. Life Sci Alliance 2021; 4:4/8/e202001000. [PMID: 34127548 PMCID: PMC8321663 DOI: 10.26508/lsa.202001000] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 05/29/2021] [Accepted: 05/31/2021] [Indexed: 02/06/2023] Open
Abstract
IL-13 is implicated in effective repair after acute lung injury and the pathogenesis of chronic diseases such as allergic asthma. Both these processes involve matrix remodelling, but understanding the specific contribution of IL-13 has been challenging because IL-13 shares receptors and signalling pathways with IL-4. Here, we used Nippostrongylus brasiliensis infection as a model of acute lung damage comparing responses between WT and IL-13-deficient mice, in which IL-4 signalling is intact. We found that IL-13 played a critical role in limiting tissue injury and haemorrhaging in the lung, and through proteomic and transcriptomic profiling, identified IL-13-dependent changes in matrix and associated regulators. We further showed a requirement for IL-13 in the induction of epithelial-derived type 2 effector molecules such as RELM-α and surfactant protein D. Pathway analyses predicted that IL-13 induced cellular stress responses and regulated lung epithelial cell differentiation by suppression of Foxa2 pathways. Thus, in the context of acute lung damage, IL-13 has tissue-protective functions and regulates epithelial cell responses during type 2 immunity.
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Affiliation(s)
- Alistair L Chenery
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK,Lydia Becker Institute for Immunology and Infection, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - Silvia Rosini
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK,Lydia Becker Institute for Immunology and Infection, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - James E Parkinson
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK,Lydia Becker Institute for Immunology and Infection, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - Jesuthas Ajendra
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK,Lydia Becker Institute for Immunology and Infection, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - Jeremy A Herrera
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - Craig Lawless
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - Brian HK Chan
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK,Lydia Becker Institute for Immunology and Infection, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - P’ng Loke
- Department of Microbiology, NYU Langone Health, New York, NY, USA
| | - Andrew S MacDonald
- Lydia Becker Institute for Immunology and Infection, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - Karl E Kadler
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK,Lydia Becker Institute for Immunology and Infection, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - Tara E Sutherland
- Lydia Becker Institute for Immunology and Infection, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - Judith E Allen
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK .,Lydia Becker Institute for Immunology and Infection, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
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26
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Cho HY, Park S, Miller L, Lee HC, Langenbach R, Kleeberger SR. Role for Mucin-5AC in Upper and Lower Airway Pathogenesis in Mice. Toxicol Pathol 2021; 49:1077-1099. [PMID: 33938323 DOI: 10.1177/01926233211004433] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Mucin-5AC (MUC5AC) is a major secreted mucin in pathogenic airways. To determine its role in mucus-related airway disorders, Muc5ac-deficient (Muc5ac-/-) and wild-type (Muc5ac+/+) mice were compared in bleomycin-induced pulmonary fibrosis, respiratory syncytial virus (RSV) disease, and ozone toxicity. Significantly greater inflammation and fibrosis by bleomycin were developed in Muc5ac-/- lungs compared to Muc5ac+/+ lungs. More severe mucous cell metaplasia in fibrotic Muc5ac-/- lungs coincided with bronchial Muc2, Muc4, and Muc5b overexpression. Airway RSV replication was higher in Muc5ac-/- than in Muc5ac+/+ during early infection. RSV-caused pulmonary epithelial death, bronchial smooth muscle thickening, and syncytia formation were more severe in Muc5ac-/- compared to Muc5ac+/+. Nasal septal damage and subepithelial mucoserous gland enrichment by RSV were greater in Muc5ac-/- than in Muc5ac+/+. Ozone exposure developed more severe nasal airway injury accompanying submucosal gland hyperplasia and pulmonary proliferation in Muc5ac-/- than in Muc5ac+/+. Ozone caused periodic acid-Schiff-positive secretion only in Muc5ac-/- nasal airways. Lung E-cadherin level was relatively lower in Muc5ac-/- than in Muc5ac+/+ basally and after bleomycin, RSV, and ozone exposure. Results indicate that MUC5AC is an essential mucosal component in acute phase airway injury protection. Subepithelial gland hyperplasia and adaptive increase of other epithelial mucins may compensate airway defense in Muc5ac-/- mice.
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Affiliation(s)
- Hye-Youn Cho
- Immunity, Inflammation and Disease Laboratory, 6857National Institute of Environmental Health Sciences, National Institutes of Health, NC, USA
| | - Soojung Park
- Signal Transduction Laboratory, 6857National Institute of Environmental Health Sciences, National Institutes of Health, NC, USA
| | - Laura Miller
- Immunity, Inflammation and Disease Laboratory, 6857National Institute of Environmental Health Sciences, National Institutes of Health, NC, USA
| | - Huei-Chen Lee
- Signal Transduction Laboratory, 6857National Institute of Environmental Health Sciences, National Institutes of Health, NC, USA
| | - Robert Langenbach
- Signal Transduction Laboratory, 6857National Institute of Environmental Health Sciences, National Institutes of Health, NC, USA
| | - Steven R Kleeberger
- Immunity, Inflammation and Disease Laboratory, 6857National Institute of Environmental Health Sciences, National Institutes of Health, NC, USA
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27
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van den Bosch WB, James AL, Tiddens HA. Structure and function of small airways in asthma patients revisited. Eur Respir Rev 2021; 30:200186. [PMID: 33472958 PMCID: PMC9488985 DOI: 10.1183/16000617.0186-2020] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 08/27/2020] [Indexed: 12/21/2022] Open
Abstract
Small airways (<2 mm in diameter) are probably involved across almost all asthma severities and they show proportionally more structural and functional abnormalities with increasing asthma severity. The structural and functional alterations of the epithelium, extracellular matrix and airway smooth muscle in small airways of people with asthma have been described over many years using in vitro studies, animal models or imaging and modelling methods. The purpose of this review was to provide an overview of these observations and to outline several potential pathophysiological mechanisms regarding the role of small airways in asthma.
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Affiliation(s)
- Wytse B. van den Bosch
- Dept of Paediatric Pulmonology and Allergology, Erasmus MC – Sophia Children’s Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Dept of Radiology and Nuclear Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Alan L. James
- Dept of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Perth, Australia
| | - Harm A.W.M. Tiddens
- Dept of Paediatric Pulmonology and Allergology, Erasmus MC – Sophia Children’s Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Dept of Radiology and Nuclear Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
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28
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Zepp JA, Morley MP, Loebel C, Kremp MM, Chaudhry FN, Basil MC, Leach JP, Liberti DC, Niethamer TK, Ying Y, Jayachandran S, Babu A, Zhou S, Frank DB, Burdick JA, Morrisey EE. Genomic, epigenomic, and biophysical cues controlling the emergence of the lung alveolus. Science 2021; 371:371/6534/eabc3172. [PMID: 33707239 PMCID: PMC8320017 DOI: 10.1126/science.abc3172] [Citation(s) in RCA: 116] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 09/16/2020] [Accepted: 01/12/2021] [Indexed: 12/15/2022]
Abstract
The lung alveolus is the functional unit of the respiratory system required for gas exchange. During the transition to air breathing at birth, biophysical forces are thought to shape the emerging tissue niche. However, the intercellular signaling that drives these processes remains poorly understood. Applying a multimodal approach, we identified alveolar type 1 (AT1) epithelial cells as a distinct signaling hub. Lineage tracing demonstrates that AT1 progenitors align with receptive, force-exerting myofibroblasts in a spatial and temporal manner. Through single-cell chromatin accessibility and pathway expression (SCAPE) analysis, we demonstrate that AT1-restricted ligands are required for myofibroblasts and alveolar formation. These studies show that the alignment of cell fates, mediated by biophysical and AT1-derived paracrine signals, drives the extensive tissue remodeling required for postnatal respiration.
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Affiliation(s)
- Jarod A. Zepp
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Penn-CHOP Lung Biology Institute, Perelman School of Medicine, University of Pennsylvania, PA, USA.,Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Division of Pulmonary Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA.,Co-Corresponding authors: ,
| | - Michael P. Morley
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Penn-CHOP Lung Biology Institute, Perelman School of Medicine, University of Pennsylvania, PA, USA.,Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Claudia Loebel
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
| | - Madison M. Kremp
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Penn-CHOP Lung Biology Institute, Perelman School of Medicine, University of Pennsylvania, PA, USA.,Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Fatima N. Chaudhry
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Maria C. Basil
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Penn-CHOP Lung Biology Institute, Perelman School of Medicine, University of Pennsylvania, PA, USA
| | - John P. Leach
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Penn-CHOP Lung Biology Institute, Perelman School of Medicine, University of Pennsylvania, PA, USA.,Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Derek C. Liberti
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Penn-CHOP Lung Biology Institute, Perelman School of Medicine, University of Pennsylvania, PA, USA.,Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Terren K. Niethamer
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Penn-CHOP Lung Biology Institute, Perelman School of Medicine, University of Pennsylvania, PA, USA.,Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Yun Ying
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Penn-CHOP Lung Biology Institute, Perelman School of Medicine, University of Pennsylvania, PA, USA.,Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Sowmya Jayachandran
- Division of Pediatric Cardiology, Department of Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA
| | - Apoorva Babu
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Penn-CHOP Lung Biology Institute, Perelman School of Medicine, University of Pennsylvania, PA, USA.,Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Su Zhou
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Penn-CHOP Lung Biology Institute, Perelman School of Medicine, University of Pennsylvania, PA, USA.,Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - David B. Frank
- Penn-CHOP Lung Biology Institute, Perelman School of Medicine, University of Pennsylvania, PA, USA.,Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Division of Pediatric Cardiology, Department of Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA
| | - Jason A. Burdick
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
| | - Edward E. Morrisey
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Penn-CHOP Lung Biology Institute, Perelman School of Medicine, University of Pennsylvania, PA, USA.,Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Co-Corresponding authors: ,
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29
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Chow RD, Majety M, Chen S. The aging transcriptome and cellular landscape of the human lung in relation to SARS-CoV-2. Nat Commun 2021; 12:4. [PMID: 33397975 PMCID: PMC7782551 DOI: 10.1038/s41467-020-20323-9] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 11/24/2020] [Indexed: 01/29/2023] Open
Abstract
Age is a major risk factor for severe coronavirus disease-2019 (COVID-19). Here, we interrogate the transcriptional features and cellular landscape of the aging human lung. By intersecting these age-associated changes with experimental data on SARS-CoV-2, we identify several factors that may contribute to the heightened severity of COVID-19 in older populations. The aging lung is transcriptionally characterized by increased cell adhesion and stress responses, with reduced mitochondria and cellular replication. Deconvolution analysis reveals that the proportions of alveolar type 2 cells, proliferating basal cells, goblet cells, and proliferating natural killer/T cells decrease with age, whereas alveolar fibroblasts, pericytes, airway smooth muscle cells, endothelial cells and IGSF21+ dendritic cells increase with age. Several age-associated genes directly interact with the SARS-CoV-2 proteome. Age-associated genes are also dysregulated by SARS-CoV-2 infection in vitro and in patients with severe COVID-19. These analyses illuminate avenues for further studies on the relationship between age and COVID-19.
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Affiliation(s)
- Ryan D Chow
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- Systems Biology Institute, Yale University, West Haven, CT, USA
- Center for Cancer Systems Biology, Yale University, West Haven, CT, USA
- M.D.-Ph.D. Program, Yale University, New Haven, CT, USA
| | - Medha Majety
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- Systems Biology Institute, Yale University, West Haven, CT, USA
- Center for Cancer Systems Biology, Yale University, West Haven, CT, USA
- The College, Yale University, New Haven, CT, 06520, USA
| | - Sidi Chen
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
- Systems Biology Institute, Yale University, West Haven, CT, USA.
- Center for Cancer Systems Biology, Yale University, West Haven, CT, USA.
- M.D.-Ph.D. Program, Yale University, New Haven, CT, USA.
- Immunobiology Program, Yale University, New Haven, CT, USA.
- Molecular Cell Biology, Genetics, and Development Program, Yale University, New Haven, CT, USA.
- Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT, USA.
- Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA.
- Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
- Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA.
- Yale Liver Center, Yale University School of Medicine, New Haven, CT, USA.
- Yale Center for Biomedical Data Science, Yale University School of Medicine, New Haven, CT, USA.
- Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT, USA.
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30
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Patel AS, Yoo S, Kong R, Sato T, Sinha A, Karam S, Bao L, Fridrikh M, Emoto K, Nudelman G, Powell CA, Beasley MB, Zhu J, Watanabe H. Prototypical oncogene family Myc defines unappreciated distinct lineage states of small cell lung cancer. SCIENCE ADVANCES 2021; 7:7/5/eabc2578. [PMID: 33514539 PMCID: PMC7846160 DOI: 10.1126/sciadv.abc2578] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 12/10/2020] [Indexed: 05/11/2023]
Abstract
Comprehensive genomic analyses of small cell lung cancer (SCLC) have revealed frequent mutually exclusive genomic amplification of MYC family members. Hence, it has been long suggested that they are functionally equivalent; however, more recently, their expression has been associated with specific neuroendocrine markers and distinct histopathology. Here, we explored a previously undescribed role of L-Myc and c-Myc as lineage-determining factors contributing to SCLC molecular subtypes and histology. Integrated transcriptomic and epigenomic analyses showed that L-Myc and c-Myc impart neuronal and non-neuroendocrine-associated transcriptional programs, respectively, both associated with distinct SCLC lineage. Genetic replacement of c-Myc with L-Myc in c-Myc-SCLC induced a neuronal state but was insufficient to induce ASCL1-SCLC. In contrast, c-Myc induced transition from ASCL1-SCLC to NEUROD1-SCLC characterized by distinct large-cell neuroendocrine carcinoma-like histopathology. Collectively, we characterize a role of historically defined general oncogenes, c-Myc and L-Myc, for regulating lineage plasticity across molecular and histological subtypes.
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Affiliation(s)
- Ayushi S Patel
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Seungyeul Yoo
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Sema4, a Mount Sinai venture, Stamford, CT 06902, USA
| | - Ranran Kong
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Department of Thoracic Surgery, The Second Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China
| | - Takashi Sato
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Abhilasha Sinha
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Sarah Karam
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Li Bao
- Ningxia People's Hospital, Yinchuan, Ningxia Province 750001, China
| | - Maya Fridrikh
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Katsura Emoto
- Department of Diagnostic Pathology, Keio University Hospital, Tokyo 160-8582, Japan
| | - German Nudelman
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Charles A Powell
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Mary Beth Beasley
- Department of Pathology and Laboratory Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Jun Zhu
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Sema4, a Mount Sinai venture, Stamford, CT 06902, USA
| | - Hideo Watanabe
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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31
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Merid SK, Bustamante M, Standl M, Sunyer J, Heinrich J, Lemonnier N, Aguilar D, Antó JM, Bousquet J, Santa-Marina L, Lertxundi A, Bergström A, Kull I, Wheelock ÅM, Koppelman GH, Melén E, Gruzieva O. Integration of gene expression and DNA methylation identifies epigenetically controlled modules related to PM 2.5 exposure. ENVIRONMENT INTERNATIONAL 2021; 146:106248. [PMID: 33212358 DOI: 10.1016/j.envint.2020.106248] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 09/24/2020] [Accepted: 10/25/2020] [Indexed: 05/28/2023]
Abstract
Air pollution has been associated with adverse health effects across the life-course. Although underlying mechanisms are unclear, several studies suggested pollutant-induced changes in transcriptomic profiles. In this meta-analysis of transcriptome-wide association studies of 656 children and adolescents from three European cohorts participating in the MeDALL Consortium, we found two differentially expressed transcript clusters (FDR p < 0.05) associated with exposure to particulate matter < 2.5 µm in diameter (PM2.5) at birth, one of them mapping to the MIR1296 gene. Further, by integrating gene expression with DNA methylation using Functional Epigenetic Modules algorithms, we identified 9 and 6 modules in relation to PM2.5 exposure at birth and at current address, respectively (including NR1I2, MAPK6, TAF8 and SCARA3). In conclusion, PM2.5 exposure at birth was linked to differential gene expression in children and adolescents. Importantly, we identified several significant interactome hotspots of gene modules of relevance for complex diseases in relation to PM2.5 exposure.
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Affiliation(s)
- Simon Kebede Merid
- Department of Clinical Sciences and Education, Karolinska Institutet, Södersjukhuset, Stockholm, Sweden
| | - Mariona Bustamante
- ISGlobal, Institute for Global Health, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain
| | - Marie Standl
- Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
| | - Jordi Sunyer
- ISGlobal, Institute for Global Health, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain; IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - Joachim Heinrich
- Institute and Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Ziemssenstraße 1, 80336 Munich, Germany; Allergy and Lung Health Unit, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia
| | - Nathanaël Lemonnier
- Institute for Advanced Biosciences, UGA-INSERM U1209-CNRS UMR5309, Allée des Alpes, France
| | - Daniel Aguilar
- Biomedical Research Networking Center in Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III, Barcelona, Spain
| | - Josep Maria Antó
- ISGlobal, Institute for Global Health, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain; IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - Jean Bousquet
- Charité, Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Comprehensive Allergy Center, Department of Dermatology and Allergy, Berlin, Germany; University Hospital, Montpellier, France; MACVIA-France, Montpellier, France
| | - Loreto Santa-Marina
- Health Research Institute-BIODONOSTIA, Basque Country, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Spain; Health Department of Basque Government, Sub-directorate of Public Health of Gipuzkoa, 20013 San Sebastian, Spain
| | - Aitana Lertxundi
- Health Research Institute-BIODONOSTIA, Basque Country, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Spain; Preventive Medicine and Public Health Department, University of Basque Country (UPV/EHU), Spain
| | - Anna Bergström
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Centre for Occupational and Environmental Medicine, Region Stockholm, Sweden
| | - Inger Kull
- Department of Clinical Sciences and Education, Karolinska Institutet, Södersjukhuset, Stockholm, Sweden; Sachs Children's Hospital, Stockholm, Sweden
| | - Åsa M Wheelock
- Respiratory Medicine Unit, Department of Medicine and Center for Molecular Medicine, Karolinska Institutet, Solna, Stockholm, Sweden
| | - Gerard H Koppelman
- University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Department of Pediatric Pulmonology and Pediatric Allergology, Groningen, the Netherlands; University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, the Netherlands
| | - Erik Melén
- Department of Clinical Sciences and Education, Karolinska Institutet, Södersjukhuset, Stockholm, Sweden; Sachs Children's Hospital, Stockholm, Sweden
| | - Olena Gruzieva
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Centre for Occupational and Environmental Medicine, Region Stockholm, Sweden.
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32
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Choi W, Yang AX, Sieve A, Kuo SH, Mudalagiriyappa S, Vieson M, Maddox CW, Nanjappa SG, Lau GW. Pulmonary Mycosis Drives Forkhead Box Protein A2 Degradation and Mucus Hypersecretion through Activation of the Spleen Tyrosine Kinase-Epidermal Growth Factor Receptor-AKT/Extracellular Signal-Regulated Kinase 1/2 Signaling. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:108-130. [PMID: 33069717 PMCID: PMC7786105 DOI: 10.1016/j.ajpath.2020.09.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 09/08/2020] [Accepted: 09/23/2020] [Indexed: 10/23/2022]
Abstract
Pulmonary mycoses are difficult to treat and detrimental to patients. Fungal infections modulate the lung immune response, induce goblet cell hyperplasia and metaplasia, and mucus hypersecretion in the airways. Excessive mucus clogs small airways and reduces pulmonary function by decreasing oxygen exchange, leading to respiratory distress. The forkhead box protein A2 (FOXA2) is a transcription factor that regulates mucus homeostasis in the airways. However, little is known whether pulmonary mycosis modulates FOXA2 function. Herein, we investigated whether Blastomyces dermatitidis and Histoplasma capsulatum-infected canine and feline lungs and airway epithelial cells could serve as higher animal models to examine the relationships between fungal pneumonia and FOXA2-regulated airway mucus homeostasis. The results indicate that fungal infection down-regulated FOXA2 expression in airway epithelial cells, with concomitant overexpression of mucin 5AC (MUC5AC) and mucin 5B (MUC5B) mucins. Mechanistic studies reveal that B. dermatitidis infection, as well as β-glucan exposure, activated the Dectin-1-SYK-epidermal growth factor receptor-AKT/extracellular signal-regulated kinase 1/2 signaling pathway that inhibits the expression of FOXA2, resulting in overexpression of MUC5AC and MUC5B in canine airway cells. Further understanding of the role of FOXA2 in mucus hypersecretion may lead to novel therapeutics against excessive mucus in both human and veterinary patients with pulmonary mycosis.
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Affiliation(s)
- Woosuk Choi
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois
| | - Alina X Yang
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois
| | - Aaron Sieve
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois
| | - Shanny H Kuo
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois
| | - Srinivasu Mudalagiriyappa
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois
| | - Miranda Vieson
- Veterinary Diagnostic Laboratory, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois; Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois
| | - Carol W Maddox
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois; Veterinary Diagnostic Laboratory, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois
| | - Som G Nanjappa
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois
| | - Gee W Lau
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois.
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33
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Improved detection of tumor suppressor events in single-cell RNA-Seq data. NPJ Genom Med 2020; 5:43. [PMID: 33083012 PMCID: PMC7541488 DOI: 10.1038/s41525-020-00151-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 08/21/2020] [Indexed: 12/17/2022] Open
Abstract
Tissue-specific transcription factors are frequently inactivated in cancer. To fully dissect the heterogeneity of such tumor suppressor events requires single-cell resolution, yet this is challenging because of the high dropout rate. Here we propose a simple yet effective computational strategy called SCIRA to infer regulatory activity of tissue-specific transcription factors at single-cell resolution and use this tool to identify tumor suppressor events in single-cell RNA-Seq cancer studies. We demonstrate that tissue-specific transcription factors are preferentially inactivated in the corresponding cancer cells, suggesting that these are driver events. For many known or suspected tumor suppressors, SCIRA predicts inactivation in single cancer cells where differential expression does not, indicating that SCIRA improves the sensitivity to detect changes in regulatory activity. We identify NKX2-1 and TBX4 inactivation as early tumor suppressor events in normal non-ciliated lung epithelial cells from smokers. In summary, SCIRA can help chart the heterogeneity of tumor suppressor events at single-cell resolution.
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34
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DNA Methylation in Chronic Obstructive Pulmonary Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1255:83-98. [PMID: 32949392 DOI: 10.1007/978-981-15-4494-1_7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
Chronic obstructive pulmonary disease (COPD) is a lung disease affected by both genetic and environmental factors. Therefore, the role of epigenetics in the pathogenesis of COPD has attracted much attention. As one of the three epigenetic mechanisms, DNA methylation has been extensively studied in COPD. The present review aims at overviewing the effect of DNA methylation on etiology, pathogenesis, pathophysiological changes, and complications of COPD. The clarification of aberrant methylation of target genes, which play important roles in the initiation and progression of COPD, will provide new disease-specific biomarker and targets for early diagnosis and therapy.
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35
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Choi W, Choe S, Lin J, Borchers MT, Kosmider B, Vassallo R, Limper AH, Lau GW. Exendin-4 restores airway mucus homeostasis through the GLP1R-PKA-PPARγ-FOXA2-phosphatase signaling. Mucosal Immunol 2020; 13:637-651. [PMID: 32034274 PMCID: PMC7664156 DOI: 10.1038/s41385-020-0262-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 01/03/2020] [Accepted: 01/21/2020] [Indexed: 02/04/2023]
Abstract
Goblet cell hyperplasia and metaplasia and excessive mucus are prominent pathologies of chronic airway diseases such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and chronic bronchitis. Chronic infection by respiratory pathogens, including Pseudomonas aeruginosa, exacerbates cyclical proinflammatory responses and mucus hypersecretion. P. aeruginosa and its virulence factor pyocyanin contribute to these pathologies by inhibiting FOXA2, a key transcriptional regulator of mucus homeostasis, through activation of antagonistic signaling pathways EGFR-AKT/ERK1/2 and IL-4/IL-13-STAT6-SPDEF. However, FOXA2-targeted therapy has not been previously explored. Here, we examined the feasibility of repurposing the incretin mimetic Exendin-4 to restore FOXA2-mediated airway mucus homeostasis. We have found that Exendin-4 restored FOXA2 expression, attenuated mucin production in COPD and CF-diseased airway cells, and reduced mucin and P. aeruginosa burden in mouse lungs. Mechanistically, Exendin-4 activated the GLP1R-PKA-PPAR-γ-dependent phosphatases PTEN and PTP1B, which inhibited key kinases within both EGFR and STAT6 signaling cascades. Our results may lead to the repurposing of Exendin-4 and other incretin mimetics to restore FOXA2 function and ultimately regulate excessive mucus in diseased airways.
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Affiliation(s)
- Woosuk Choi
- Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Shawn Choe
- Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Jingjun Lin
- Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Michael T Borchers
- Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Cincinnati Veteran's Affairs Medical Center, Cincinnati, OH, 45267, USA
| | - Beata Kosmider
- Department of Physiology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
- Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
- Center for Inflammation, Translational and Clinical Lung Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Robert Vassallo
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA
| | - Andrew H Limper
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA
| | - Gee W Lau
- Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
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36
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Paranjapye A, Mutolo MJ, Ebron JS, Leir SH, Harris A. The FOXA1 transcriptional network coordinates key functions of primary human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 2020; 319:L126-L136. [PMID: 32432922 DOI: 10.1152/ajplung.00023.2020] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
The differentiated functions of the human airway epithelium are coordinated by a complex network of transcription factors. These include the pioneer factors Forkhead box A1 and A2 (FOXA1 and FOXA2), which are well studied in several tissues, but their role in airway epithelial cells is poorly characterized. Here, we define the cistrome of FOXA1 and FOXA2 in primary human bronchial epithelial (HBE) cells by chromatin immunoprecipitation with deep-sequencing (ChIP-seq). Next, siRNA-mediated depletion of each factor is used to investigate their transcriptome by RNA-seq. We found that, as predicted from their DNA-binding motifs, genome-wide occupancy of the two factors showed substantial overlap; however, their global impact on gene expression differed. FOXA1 is an abundant transcript in HBE cells, while FOXA2 is expressed at low levels, and both these factors likely exhibit autoregulation and cross-regulation. FOXA1 regulated loci are involved in cell adhesion and the maintenance of epithelial cell identity, particularly through repression of genes associated with epithelial to mesenchymal transition (EMT). FOXA1 also directly targets other transcription factors with a known role in the airway epithelium such as SAM-pointed domain-containing Ets-like factor (SPDEF). The intersection of the cistrome and transcriptome for FOXA1 revealed enrichment of genes involved in epithelial development and tissue morphogenesis. Moreover, depletion of FOXA1 was shown to reduce the transepithelial resistance of HBE cells, confirming the role of this factor in maintaining epithelial barrier integrity.
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Affiliation(s)
- Alekh Paranjapye
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio
| | - Michael J Mutolo
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio
| | - Jey Sabith Ebron
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio
| | - Shih-Hsing Leir
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio
| | - Ann Harris
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio
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37
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Frey A, Lunding LP, Ehlers JC, Weckmann M, Zissler UM, Wegmann M. More Than Just a Barrier: The Immune Functions of the Airway Epithelium in Asthma Pathogenesis. Front Immunol 2020; 11:761. [PMID: 32411147 PMCID: PMC7198799 DOI: 10.3389/fimmu.2020.00761] [Citation(s) in RCA: 135] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 04/03/2020] [Indexed: 12/11/2022] Open
Abstract
Allergic bronchial asthma is a chronic disease of the airways that is characterized by symptoms like respiratory distress, chest tightness, wheezing, productive cough, and acute episodes of broncho-obstruction. This symptom-complex arises on the basis of chronic allergic inflammation of the airway wall. Consequently, the airway epithelium is central to the pathogenesis of this disease, because its multiple abilities directly have an impact on the inflammatory response and thus the formation of the disease. In turn, its structure and functions are markedly impaired by the inflammation. Hence, the airway epithelium represents a sealed, self-cleaning barrier, that prohibits penetration of inhaled allergens, pathogens, and other noxious agents into the body. This barrier is covered with mucus that further contains antimicrobial peptides and antibodies that are either produced or specifically transported by the airway epithelium in order to trap these particles and to remove them from the body by a process called mucociliary clearance. Once this first line of defense of the lung is overcome, airway epithelial cells are the first cells to get in contact with pathogens, to be damaged or infected. Therefore, these cells release a plethora of chemokines and cytokines that not only induce an acute inflammatory reaction but also have an impact on the alignment of the following immune reaction. In case of asthma, all these functions are impaired by the already existing allergic immune response that per se weakens the barrier integrity and self-cleaning abilities of the airway epithelium making it more vulnerable to penetration of allergens as well as of infection by bacteria and viruses. Recent studies indicate that the history of allergy- and pathogen-derived insults can leave some kind of memory in these cells that can be described as imprinting or trained immunity. Thus, the airway epithelium is in the center of processes that lead to formation, progression and acute exacerbation of asthma.
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Affiliation(s)
- Andreas Frey
- Division of Mucosal Immunology and Diagnostics, Research Center Borstel, Borstel, Germany.,Airway Research Center North, German Center for Lung Research (DZL), Borstel, Germany
| | - Lars P Lunding
- Airway Research Center North, German Center for Lung Research (DZL), Borstel, Germany.,Division of Asthma Exacerbation & Regulation, Research Center Borstel, Borstel, Germany
| | - Johanna C Ehlers
- Airway Research Center North, German Center for Lung Research (DZL), Borstel, Germany.,Division of Experimental Pneumology, Research Center Borstel, Borstel, Germany
| | - Markus Weckmann
- Airway Research Center North, German Center for Lung Research (DZL), Borstel, Germany.,Department of Pediatric Pulmonology and Allergology, University Children's Hospital, Lübeck, Germany
| | - Ulrich M Zissler
- Center of Allergy & Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Munich, Germany.,Member of the German Center for Lung Research (DZL), CPC-M, Munich, Germany
| | - Michael Wegmann
- Airway Research Center North, German Center for Lung Research (DZL), Borstel, Germany.,Division of Asthma Exacerbation & Regulation, Research Center Borstel, Borstel, Germany
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38
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Portelli MA, Dijk FN, Ketelaar ME, Shrine N, Hankinson J, Bhaker S, Grotenboer NS, Obeidat M, Henry AP, Billington CK, Shaw D, Johnson SR, Pogson ZE, Fogarty A, McKeever TM, Nickle DC, Bossé Y, van den Berge M, Faiz A, Brouwer S, Vonk JM, de Vos P, Brandsma CA, Vermeulen CJ, Singapuri A, Heaney LG, Mansur AH, Chaudhuri R, Thomson NC, Holloway JW, Lockett GA, Howarth PH, Niven R, Simpson A, Blakey JD, Tobin MD, Postma DS, Hall IP, Wain LV, Nawijn MC, Brightling CE, Koppelman GH, Sayers I. Phenotypic and functional translation of IL1RL1 locus polymorphisms in lung tissue and asthmatic airway epithelium. JCI Insight 2020; 5:132446. [PMID: 32324168 PMCID: PMC7205441 DOI: 10.1172/jci.insight.132446] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 03/12/2020] [Indexed: 12/22/2022] Open
Abstract
The IL1RL1 (ST2) gene locus is robustly associated with asthma; however, the contribution of single nucleotide polymorphisms (SNPs) in this locus to specific asthma subtypes and the functional mechanisms underlying these associations remain to be defined. We tested for association between IL1RL1 region SNPs and characteristics of asthma as defined by clinical and immunological measures and addressed functional effects of these genetic variants in lung tissue and airway epithelium. Utilizing 4 independent cohorts (Lifelines, Dutch Asthma GWAS [DAG], Genetics of Asthma Severity and Phenotypes [GASP], and Manchester Asthma and Allergy Study [MAAS]) and resequencing data, we identified 3 key signals associated with asthma features. Investigations in lung tissue and primary bronchial epithelial cells identified context-dependent relationships between the signals and IL1RL1 mRNA and soluble protein expression. This was also observed for asthma-associated IL1RL1 nonsynonymous coding TIR domain SNPs. Bronchial epithelial cell cultures from asthma patients, exposed to exacerbation-relevant stimulations, revealed modulatory effects for all 4 signals on IL1RL1 mRNA and/or protein expression, suggesting SNP-environment interactions. The IL1RL1 TIR signaling domain haplotype affected IL-33–driven NF-κB signaling, while not interfering with TLR signaling. In summary, we identify that IL1RL1 genetic signals potentially contribute to severe and eosinophilic phenotypes in asthma, as well as provide initial mechanistic insight, including genetic regulation of IL1RL1 isoform expression and receptor signaling.
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Affiliation(s)
- Michael A Portelli
- Division of Respiratory Medicine, NIHR, Nottingham Biomedical Research Centre, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - F Nicole Dijk
- Department of Pediatric Pulmonology and Pediatric Allergology, and
| | - Maria E Ketelaar
- Division of Respiratory Medicine, NIHR, Nottingham Biomedical Research Centre, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom.,Department of Pediatric Pulmonology and Pediatric Allergology, and.,Department of Pathology and Medical Biology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, University of Groningen, Groningen, Netherlands
| | - Nick Shrine
- Department of Health Sciences, University of Leicester, Leicester, United Kingdom
| | - Jenny Hankinson
- Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
| | - Sangita Bhaker
- Division of Respiratory Medicine, NIHR, Nottingham Biomedical Research Centre, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Néomi S Grotenboer
- Department of Pediatric Pulmonology and Pediatric Allergology, and.,Department of Pathology and Medical Biology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, University of Groningen, Groningen, Netherlands
| | - Ma'en Obeidat
- The University of British Columbia Center for Heart Lung Innovation, St. Paul's Hospital Vancouver, Vancouver, British Columbia, Canada
| | - Amanda P Henry
- Division of Respiratory Medicine, NIHR, Nottingham Biomedical Research Centre, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Charlotte K Billington
- Division of Respiratory Medicine, NIHR, Nottingham Biomedical Research Centre, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Dominick Shaw
- Division of Respiratory Medicine, NIHR, Nottingham Biomedical Research Centre, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Simon R Johnson
- Division of Respiratory Medicine, NIHR, Nottingham Biomedical Research Centre, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Zara Ek Pogson
- Division of Epidemiology and Public Health, University of Nottingham, Nottingham, United Kingdom
| | - Andrew Fogarty
- Division of Epidemiology and Public Health, University of Nottingham, Nottingham, United Kingdom
| | - Tricia M McKeever
- Division of Epidemiology and Public Health, University of Nottingham, Nottingham, United Kingdom
| | - David C Nickle
- Departments of Genetics and Pharmacogenomics, Merck Research Laboratories, Boston, Massachusetts, USA
| | - Yohan Bossé
- Institut universitaire de cardiologie et de pneumologie de Québec, Department of Molecular Medicine, Laval University, Québec, Canada
| | - Maarten van den Berge
- University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Department of Pulmonary Diseases, and
| | - Alen Faiz
- University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Department of Pulmonary Diseases, and
| | - Sharon Brouwer
- Department of Pathology and Medical Biology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, University of Groningen, Groningen, Netherlands
| | - Judith M Vonk
- Department of Epidemiology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, University of Groningen, Groningen, Netherlands
| | - Paul de Vos
- Department of Pathology and Medical Biology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, University of Groningen, Groningen, Netherlands
| | - Corry-Anke Brandsma
- Department of Pathology and Medical Biology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, University of Groningen, Groningen, Netherlands
| | - Cornelis J Vermeulen
- Department of Pathology and Medical Biology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, University of Groningen, Groningen, Netherlands
| | - Amisha Singapuri
- Respiratory sciences, University of Leicester, Glenfield Hospital, Leicester, United Kingdom
| | - Liam G Heaney
- Centre for Experimental Medicine, Queens University of Belfast, Belfast, United Kingdom
| | - Adel H Mansur
- Department of Respiratory Medicine, Birmingham Heartlands Hospital and University of Birmingham, Birmingham, United Kingdom
| | - Rekha Chaudhuri
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
| | - Neil C Thomson
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
| | - John W Holloway
- Department of Human Development and.,Department of Health & Clinical and Experimental Sciences, Faculty of Medicine and NIH Research (NIHR), Southampton Biomedical Research Centre, University of Southampton, Southampton, United Kingdom
| | - Gabrielle A Lockett
- Department of Human Development and.,Department of Health & Clinical and Experimental Sciences, Faculty of Medicine and NIH Research (NIHR), Southampton Biomedical Research Centre, University of Southampton, Southampton, United Kingdom
| | - Peter H Howarth
- Department of Human Development and.,Department of Health & Clinical and Experimental Sciences, Faculty of Medicine and NIH Research (NIHR), Southampton Biomedical Research Centre, University of Southampton, Southampton, United Kingdom
| | - Robert Niven
- Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
| | - Angela Simpson
- Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
| | - John D Blakey
- Respiratory Medicine, Sir Charles Gairdner Hospital, Perth, Australia
| | - Martin D Tobin
- Department of Health Sciences, University of Leicester, Leicester, United Kingdom.,NIHR, Leicester Respiratory Biomedical Research Centre, University of Leicester, Leicester, United Kingdom
| | - Dirkje S Postma
- University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Department of Pulmonary Diseases, and
| | - Ian P Hall
- Division of Respiratory Medicine, NIHR, Nottingham Biomedical Research Centre, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Louise V Wain
- Department of Health Sciences, University of Leicester, Leicester, United Kingdom.,NIHR, Leicester Respiratory Biomedical Research Centre, University of Leicester, Leicester, United Kingdom
| | - Martijn C Nawijn
- Department of Pathology and Medical Biology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, University of Groningen, Groningen, Netherlands
| | - Christopher E Brightling
- Respiratory sciences, University of Leicester, Glenfield Hospital, Leicester, United Kingdom.,NIHR, Leicester Respiratory Biomedical Research Centre, University of Leicester, Leicester, United Kingdom
| | | | - Ian Sayers
- Division of Respiratory Medicine, NIHR, Nottingham Biomedical Research Centre, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
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Choi W, Choe S, Lau GW. Inactivation of FOXA2 by Respiratory Bacterial Pathogens and Dysregulation of Pulmonary Mucus Homeostasis. Front Immunol 2020; 11:515. [PMID: 32269574 PMCID: PMC7109298 DOI: 10.3389/fimmu.2020.00515] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 03/06/2020] [Indexed: 01/21/2023] Open
Abstract
Forkhead box (FOX) proteins are transcriptional factors that regulate various cellular processes. This minireview provides an overview of FOXA2 functions, with a special emphasis on the regulation airway mucus homeostasis in both healthy and diseased lungs. FOXA2 plays crucial roles during lung morphogenesis, surfactant protein production, goblet cell differentiation and mucin expression. In healthy airways, FOXA2 exerts a tight control over goblet cell development and mucin biosynthesis. However, in diseased airways, microbial infections and proinflammatory responses deplete FOXA2 expression, resulting in uncontrolled goblet cell hyperplasia and metaplasia, mucus hypersecretion, and impaired mucociliary clearance of pathogens. Furthermore, accumulated mucus clogs the airways and creates a niche environment for persistent microbial colonization and infection, leading to acute exacerbation and deterioration of pulmonary function in patients with chronic lung diseases. Various studies have shown that FOXA2 inhibition is mediated through induction of antagonistic EGFR and IL-13R-STAT6 signaling pathways as well as through posttranslational modifications induced by microbial infections. An improved understanding of how bacterial pathogens inactivate FOXA2 may pave the way for developing therapeutics that preserve the protein's function, which in turn, will improve the mucus status and mucociliary clearance of pathogens, reduce microbial-mediated acute exacerbation and restore lung function in patients with chronic lung diseases.
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Affiliation(s)
- Woosuk Choi
- Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Shawn Choe
- Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Gee W Lau
- Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL, United States
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40
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Fakler F, Aykutlu U, Brcic L, Eidenhammer S, Thueringer A, Kashofer K, Kulka J, Timens W, Popper H. Atypical goblet cell hyperplasia occurs in CPAM 1, 2, and 3, and is a probable precursor lesion for childhood adenocarcinoma. Virchows Arch 2019; 476:843-854. [PMID: 31858221 DOI: 10.1007/s00428-019-02732-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 11/26/2019] [Accepted: 12/09/2019] [Indexed: 10/25/2022]
Abstract
Congenital pulmonary airway malformation (CPAM) is a developmental disorder. Types 1-2-3 are the more common ones. Atypical goblet cell hyperplasia (AGCH) in CPAM might be a precursor lesion for pulmonary adenocarcinomas. In nine out of 33 CPAM cases, types 1-3 showed foci of goblet cell proliferations. As these cells completely replace normal epithelium, we prefer to name these proliferations AGCH. In 5 cases, adenocarcinomas were seen (AC). All cases were analyzed for proteins possibly being associated with CPAM development: fibroblast growth factor 10 (FGF10) and receptor 2 (FGFR2), forkhead box A1 (FOXA1) and A2 (FOXA2), MUC protein 5AC (MUC5AC), human epidermal growth factor receptor 2 (erbB2, HER2/neu), hepatocyte nuclear factor 4α (HNF4α), SOX2, and Ying Yang protein 1 (YY1). By next generation sequencing, AGCH and adenocarcinomas were evaluated for driver mutations. Expression for FGF10, FGFR2, FOXA1, and FOXA2 was seen in CPAM epithelium and stroma, but not differently in AGCH and AC. SOX2 was positive in CPAM epithelium and AGCH, however weakly in AC. YY1 and MUC5AC showed more intense staining in AGCH and AC than in CPAM epithelium. HER2 was intensely expressed in AC and less intensely in AGCH, but not in CPAM epithelium. KRAS mutation in exon 2 was detected in all AGCH and AC, but was absent in CPAM epithelia. AGCH can arise in CPAM types 1-3. Oncogenic KRAS mutation seems to be the oncogenic driver already in AGCH, proving its role as a precursor lesion for adenocarcinoma. It might upregulate HER2 at the protein level. YY1 seems to be involved in carcinogenesis.
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Affiliation(s)
- Fabian Fakler
- Diagnostic and Research Institute of Pathology, Medical University Graz, Neue Stiftingtalstrasse 6, 8036, Graz, Austria
| | - Umut Aykutlu
- Department of Pathology, Erzurum Regional Training and Research Hospital, Erzurum, Turkey
| | - Luka Brcic
- Diagnostic and Research Institute of Pathology, Medical University Graz, Neue Stiftingtalstrasse 6, 8036, Graz, Austria
| | - Sylvia Eidenhammer
- Diagnostic and Research Institute of Pathology, Medical University Graz, Neue Stiftingtalstrasse 6, 8036, Graz, Austria
| | - Andrea Thueringer
- Diagnostic and Research Institute of Pathology, Medical University Graz, Neue Stiftingtalstrasse 6, 8036, Graz, Austria
| | - Karl Kashofer
- Diagnostic and Research Institute of Pathology, Medical University Graz, Neue Stiftingtalstrasse 6, 8036, Graz, Austria
| | - Janina Kulka
- 2nd Department of Pathology, Semmelweis University Budapest, Budapest, Hungary
| | - Wim Timens
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center, Groningen, The Netherlands
| | - Helmut Popper
- Diagnostic and Research Institute of Pathology, Medical University Graz, Neue Stiftingtalstrasse 6, 8036, Graz, Austria.
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41
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Kurrle Y, Kunesch K, Bogusch S, Schweickert A. Serotonin and MucXS release by small secretory cells depend on
Xpod
, a SSC specific marker gene. Genesis 2019; 58:e23344. [DOI: 10.1002/dvg.23344] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 10/24/2019] [Accepted: 10/25/2019] [Indexed: 11/07/2022]
Affiliation(s)
- Yvonne Kurrle
- Institute of ZoologyUniversity of Hohenheim Stuttgart Germany
| | | | - Susanne Bogusch
- Institute of ZoologyUniversity of Hohenheim Stuttgart Germany
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42
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Warren R, O'Reilly MA. An Elusive Fox that Suppresses Scgb1a1 in Asthma Has Been Found. Am J Respir Cell Mol Biol 2019; 60:615-617. [PMID: 30726101 PMCID: PMC6543739 DOI: 10.1165/rcmb.2019-0019ed] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Affiliation(s)
- Rachel Warren
- 1 School of Medicine and Dentistry University of Rochester Rochester, New York
| | - Michael A O'Reilly
- 1 School of Medicine and Dentistry University of Rochester Rochester, New York
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Abstract
Asthma is a genetically and phenotypically complex disease that has a major impact on global health. Signs and symptoms of asthma are caused by the obstruction of airflow through the airways. The epithelium that lines the airways plays a major role in maintaining airway patency and in host defense. The epithelium initiates responses to inhaled or aspirated substances, including allergens, viruses, and bacteria, and epithelial-derived cytokines are important in the recruitment and activation of immune cells in the airway. Changes in the structure and function of the airway epithelium are a prominent feature of asthma. Approximately half of individuals with asthma have evidence of active type 2 immune responses in the airway. In these individuals, epithelial cytokines promote type 2 responses, and responses to type 2 cytokines result in increased epithelial mucus production and other effects that cause airway obstruction. Recent work also implicates other epithelial responses, including interleukin-17, interferon and ER stress responses, that may contribute to asthma pathogenesis and provide new targets for therapy.
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Affiliation(s)
- Luke R Bonser
- Lung Biology Center, University of California San Francisco, San Francisco, CA, United States
| | - David J Erle
- Lung Biology Center, University of California San Francisco, San Francisco, CA, United States.
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The Possible Pathogenesis of Idiopathic Pulmonary Fibrosis considering MUC5B. BIOMED RESEARCH INTERNATIONAL 2019; 2019:9712464. [PMID: 31309122 PMCID: PMC6594326 DOI: 10.1155/2019/9712464] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 04/18/2019] [Accepted: 05/08/2019] [Indexed: 12/27/2022]
Abstract
Background Overexpression of the MUC5B protein is associated with idiopathic pulmonary fibrosis (IPF), but little information is available regarding the pathogenic effects and regulatory mechanisms of overexpressed MUC5B in IPF. Main Body The overexpression of MUC5B in terminal bronchi and honeycomb cysts produces mucosal host defensive dysfunction in the distal airway which may play an important role in the development of IPF. This review addresses the possible association of overexpression of MUC5B, with MUC5B promoter polymorphism, MUC5B gene epigenetic changes, effects of some transcriptional factors, and inflammatory mediators in IPF. In addition, the associated signaling pathways which may influence the expression of MUC5B are also discussed. Conclusion This work has important implications for further exploration of the mechanisms of overexpression of MUC5B in IPF, and future personalized treatment.
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45
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Yeganeh B, Lee J, Ermini L, Lok I, Ackerley C, Post M. Autophagy is required for lung development and morphogenesis. J Clin Invest 2019; 129:2904-2919. [PMID: 31162135 DOI: 10.1172/jci127307] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 04/12/2019] [Indexed: 12/30/2022] Open
Abstract
Bronchopulmonary dysplasia (BPD) remains a major respiratory illness in extremely premature infants. The biological mechanisms leading to BPD are not fully understood, although an arrest in lung development has been implicated. The current study aimed to investigate the occurrence of autophagy in the developing mouse lung and its regulatory role in airway branching and terminal sacculi formation. We found 2 windows of epithelial autophagy activation in the developing mouse lung, both resulting from AMPK activation. Inhibition of AMPK-mediated autophagy led to reduced lung branching in vitro. Conditional deletion of beclin 1 (Becn1) in mouse lung epithelial cells (Becn1Epi-KO), either at early (E10.5) or late (E16.5) gestation, resulted in lethal respiratory distress at birth or shortly after. E10.5 Becn1Epi-KO lungs displayed reduced airway branching and sacculi formation accompanied by impaired vascularization, excessive epithelial cell death, reduced mesenchymal thinning of the interstitial walls, and delayed epithelial maturation. E16.5 Becn1Epi-KO lungs had reduced terminal air sac formation and vascularization and delayed distal epithelial differentiation, a pathology similar to that seen in infants with BPD. Taken together, our findings demonstrate that intrinsic autophagy is an important regulator of lung development and morphogenesis and may contribute to the BPD phenotype when impaired.
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Affiliation(s)
- Behzad Yeganeh
- Program in Translational Medicine, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children
| | - Joyce Lee
- Program in Translational Medicine, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children.,Institute of Medical Science, and
| | - Leonardo Ermini
- Program in Translational Medicine, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children
| | - Irene Lok
- Program in Translational Medicine, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children
| | - Cameron Ackerley
- Program in Translational Medicine, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children.,Departments of Physiology and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Martin Post
- Program in Translational Medicine, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children.,Institute of Medical Science, and.,Departments of Physiology and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
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Malvin NP, Kern JT, Liu TC, Brody SL, Stappenbeck TS. Autophagy proteins are required for club cell structure and function in airways. Am J Physiol Lung Cell Mol Physiol 2019; 317:L259-L270. [PMID: 31116580 DOI: 10.1152/ajplung.00394.2018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Epithelial cells that line lung airways produce and secrete proteins with important roles in barrier function and host defense. Secretion of airway goblet cells is controlled by autophagy proteins during inflammatory conditions, resulting in accumulation of mucin proteins. We hypothesized that autophagy proteins would also be important in the function of club cells, dominant secretory airway epithelial cells that are dysregulated in chronic lung disease. We found that in the absence of an inflammatory stimulus, mice with club cells deficient for the autophagy protein Atg5 had a markedly diminished expression of secreted host defense proteins secretoglobulin family 1A, member 1 (Scgb1a1) and surfactant proteins A1 and D (Sftpa1 and Sftpd), as well as abnormal club cell morphology. Adult mice with targeted loss of Atg5 also showed diminished levels of host defense proteins in regenerating cells following ablation with naphthalene. A mouse strain with global deficiency of Atg16-like 1 (Atg16l1), an Atg5 binding partner, had a similar loss of host defense proteins and abnormal club cell morphology. Cigarette smoke exposure reduced levels of Scgb1a1 in wild-type mice as expected. Smoke exposure was not required to trigger club cell abnormalities in mice bearing the human ATG16 variant Atg16l1T300A/T300A, which had low Scgb1a1 levels independent of this environmental stress. Evaluation of lung tissues from former smokers with severe chronic obstructive pulmonary disease showed evidence of reduced autophagy and SCGB1A1 expression in club cells. Thus, autophagy proteins are required for the function of club cells, independent of the cellular stress of cigarette smoke, with roles that appear to be distinct from those of other secretory cell types.
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Affiliation(s)
- Nicole P Malvin
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri
| | - Justin T Kern
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri
| | - Ta-Chiang Liu
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri
| | - Steven L Brody
- Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Thaddeus S Stappenbeck
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri
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47
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Perkins TN, Oczypok EA, Dutz RE, Donnell ML, Myerburg MM, Oury TD. The receptor for advanced glycation end products is a critical mediator of type 2 cytokine signaling in the lungs. J Allergy Clin Immunol 2019; 144:796-808.e12. [PMID: 30940519 DOI: 10.1016/j.jaci.2019.03.019] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 03/05/2019] [Accepted: 03/18/2019] [Indexed: 01/05/2023]
Abstract
BACKGROUND Asthma is estimated to effect more than 300 million persons worldwide, leading to nearly 250,000 deaths annually. The majority of patients with mild-to-severe asthma have what is deemed "type-2 high" asthma, which is driven by the prototypical type 2 cytokines IL-4, IL-5, and IL-13. Studies have indicated that the receptor for advanced glycation end products (RAGE) is a critical molecule in the pathogenesis of experimental asthma/allergic airway inflammation. More specifically, RAGE expressed on stromal cells, rather than hematopoietic cells, is critical to induction of asthma/allergic airway inflammation by driving type 2 inflammatory responses. However, the role of RAGE in directly mediating type 2 cytokine signaling has never been investigated. OBJECTIVE The goal of this study was to test the hypothesis that RAGE mediates type 2 cytokine-induced signal transduction, airway inflammation, and mucus metaplasia in the lungs. METHODS Wild-type (WT) and RAGE knockout (RAGE-/-) mice, were intranasally administered rIL-5/rIL-13 or rIL-4 alone, and signal transducer and activator of transcription 6 (STAT6) signaling, airway inflammation, and mucus metaplasia were assessed. A RAGE small-molecule antagonist was used to determine the effects of pharmacologically inhibiting RAGE on type 2 cytokine-induced effects. RESULTS Administration of type 2 cytokines induced pronounced airway inflammation and mucus metaplasia in WT mice, which was nearly completely abrogated in RAGE-/- mice. In addition, treatment with a RAGE-specific antagonist diminished the effects of type 2 cytokines in WT mice and in primary human bronchial epithelial cell cultures. Genetic ablation or pharmacologic inhibition of RAGE blocks the effects of IL-13 and IL-4 by inhibiting sustained STAT6 activation and downstream target gene expression in mice and in human bronchial epithelial cells. CONCLUSIONS This study is the first to indicate that RAGE is a critical component of type 2 cytokine signal transduction mechanisms, which is a driving force behind type 2-high asthma.
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Affiliation(s)
- Timothy N Perkins
- Department of Pathology, University of Pittsburgh, School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pa; Department of Pediatrics, Division of Pulmonary, Allergy, and Clinical Immunology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pa.
| | - Elizabeth A Oczypok
- Department of Medicine, University of Pittsburgh, School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pa
| | - Regina E Dutz
- Department of Pathology, University of Pittsburgh, School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pa
| | - Mason L Donnell
- Department of Pathology, University of Pittsburgh, School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pa
| | - Michael M Myerburg
- Department of Medicine, University of Pittsburgh, School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pa
| | - Tim D Oury
- Department of Pathology, University of Pittsburgh, School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pa.
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48
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The long noncoding RNA Falcor regulates Foxa2 expression to maintain lung epithelial homeostasis and promote regeneration. Genes Dev 2019; 33:656-668. [PMID: 30923168 PMCID: PMC6546060 DOI: 10.1101/gad.320523.118] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 03/06/2019] [Indexed: 01/09/2023]
Abstract
Swarr et al. identified a regulatory feedback loop between Foxa2 and a downstream lncRNA, Falcor, in the lung. Transcription factors (TFs) are dosage-sensitive master regulators of gene expression, with haploinsufficiency frequently leading to life-threatening disease. Numerous mechanisms have evolved to tightly regulate the expression and activity of TFs at the transcriptional, translational, and posttranslational levels. A subset of long noncoding RNAs (lncRNAs) is spatially correlated with transcription factors in the genome, but the regulatory relationship between these lncRNAs and their neighboring TFs is unclear. We identified a regulatory feedback loop between the TF Foxa2 and a downstream lncRNA, Falcor (Foxa2-adjacent long noncoding RNA). Foxa2 directly represses Falcor expression by binding to its promoter, while Falcor functions in cis to positively regulate the expression of Foxa2. In the lung, loss of Falcor is sufficient to lead to chronic inflammatory changes and defective repair after airway epithelial injury. Moreover, disruption of the Falcor–Foxa2 regulatory feedback loop leads to altered cell adhesion and migration, in turn resulting in chronic peribronchial airway inflammation and goblet cell metaplasia. These data reveal that the lncRNA Falcor functions within a regulatory feedback loop to fine-tune the expression of Foxa2, maintain airway epithelial homeostasis, and promote regeneration.
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49
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Feng F, Du J, Meng Y, Guo F, Feng C. Louqin Zhisou Decoction Inhibits Mucus Hypersecretion for Acute Exacerbation of Chronic Obstructive Pulmonary Disease Rats by Suppressing EGFR-PI3K-AKT Signaling Pathway and Restoring Th17/Treg Balance. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2019; 2019:6471815. [PMID: 30800170 PMCID: PMC6360623 DOI: 10.1155/2019/6471815] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 12/23/2018] [Indexed: 01/05/2023]
Abstract
Airway mucus hypersecretion is the main pathogenic factor in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and the control of mucus secretion is closely associated with survival. Louqin Zhisou decoction (LQZS) has been found to improve lung function and reduce sputum in AECOPD patients, but the mechanism remains unclear. This study aimed to explore the mechanism of LQZS against mucus hypersecretion in lung tissues of rat AECOPD model. Wistar rats were used to establish AECOPD model by intratracheal instillation of LPS in combination with the continuous cigarette smoking. Rats were administrated LQZS/clarithromycin (CAM)/distilled water via gavage every day and all rats were sacrificed after 30 days. BALF and lung tissues were obtained. Lung morphology, cytokines levels, MUC5AC mRNA transcription and protein expression, phosphorylation of the EGFR-PI3K-AKT signaling pathway, and molecules involved in Th17/Treg balance were evaluated. The results demonstrated that LQZS protected rats from decline in pulmonary function and ameliorated lung injury. LQZS treatment decreased the number of goblet cells in airway and suppressed MUC5AC mRNA and protein expression of lung tissues. Furthermore, LQZS attenuated the level of phospho-EGFR, phospho-PI3K and phospho-AKT in AECOPD rats. In addition, LQZS could inhibit the production of proinflammatory cytokines in BALF, including IL-6 and IL-17A and downregulate the secretion of NE and MCP-1, indicating that LQZS could limit inflammatory responses in AECOPD. Moreover, LQZS reversed RORγt and Foxp3 expression, the key transcription factors of Th17 and Treg, respectively. In conclusion, this research demonstrated the inhibitory effects of LQZS against mucus hypersecretion in AECOPD via suppressing EGFR-PI3K-AKT signaling pathway and restoring Th17/Treg balance.
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Affiliation(s)
- Feng Feng
- Beijing University of Chinese Medicine, Beijing 100029, China
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
- Peking University People's Hospital, Beijing 100044, China
| | - Jianchao Du
- Beijing Hospital of Traditional Chinese Medicine Shunyi Branch, Beijing 101300, China
| | - Yufeng Meng
- Peking University People's Hospital, Beijing 100044, China
| | - Fang Guo
- Peking University People's Hospital, Beijing 100044, China
| | - Cuiling Feng
- Peking University People's Hospital, Beijing 100044, China
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50
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Kubo F, Ariestanti DM, Oki S, Fukuzawa T, Demizu R, Sato T, Sabirin RM, Hirose S, Nakamura N. Loss of the adhesion G-protein coupled receptor ADGRF5 in mice induces airway inflammation and the expression of CCL2 in lung endothelial cells. Respir Res 2019; 20:11. [PMID: 30654796 PMCID: PMC6337809 DOI: 10.1186/s12931-019-0973-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Accepted: 01/02/2019] [Indexed: 01/09/2023] Open
Abstract
Background Adhesion G-protein coupled receptor F5 (ADGRF5) was recently identified as an essential regulator of pulmonary surfactant homeostasis in alveolar type II cells. We previously showed that in addition to abnormal surfactant accumulation, Adgrf5-deficient (Adgrf5−/−) mice exhibit emphysema-like signs, suggesting a possible role for ADGRF5 in immune regulation. Here, we extended the phenotypic analysis of Adgrf5−/− mice to help understand its biological role in the lung, and especially in immune regulation. Methods Histological features of lungs were evaluated by Alcian blue and Masson’s trichrome staining. Quantitative real-time PCR (qPCR) and western blot analyses were performed to analyze the differential expression of genes/proteins related to airway inflammation in lungs between wildtype and Adgrf5−/− mice. Acid–base status was assessed by performing blood gas tests and urine pH measurements. Inflammatory cell counting was performed using Giemsa-stained bronchoalveolar lavage cells. Serum IgE concentrations were determined by enzyme-linked immunosorbent assay. The expression of Ccl2, S100a8, S100a9, and Saa3 in primary lung endothelial cells (ECs) was determined by qPCR and/or western blotting. Finally, the effect of administrating RS504393 to 2-week-old Adgrf5−/− mice on gene expression in the lungs was analyzed by qPCR. Results Adgrf5−/− mice exhibited several features of chronic airway inflammation (mucous cell metaplasia, mucus hyperproduction, subepithelial fibrosis, respiratory acidosis, high serum IgE, mast cell accumulation, and neutrophilia) in parallel with elevated expression of genes involved in mucous cell metaplasia (Muc5ac, Muc5b, Slc26a4, and Clca1), fibrosis (Tgfb1, Col1a1, Fn1, and Tnc), and type 2 immune response (Il4, Il5, Il13, IL-25, and IL-33) at 12 and/or 30 weeks of age. In contrast, mRNA expression of Ccl2, S100a8, and S100a9 was upregulated in embryonic or neonatal Adgrf5−/− lungs as well as in lung ECs of Adgrf5−/− mice at 1 week of age. RS504393 treatment suppressed the upregulation of S100a8, S100a9, Slc26a4, and Il5 in Adgrf5−/− lungs. Conclusions Targeted disruption of ADGRF5 results in the development of airway inflammation, which is likely mediated by the type 2 immune response and possibly CCL2-mediated inflammation. ADGRF5 also has a potential role in the regulation of genes encoding CCL2 in lung ECs, thereby maintaining immune homeostasis. Electronic supplementary material The online version of this article (10.1186/s12931-019-0973-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Fumimasa Kubo
- Department of Life Science and Technology, Tokyo Institute of Technology, 4259-B13 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan
| | - Donna Maretta Ariestanti
- Department of Life Science and Technology, Tokyo Institute of Technology, 4259-B13 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan
| | - Souta Oki
- Department of Life Science and Technology, Tokyo Institute of Technology, 4259-B13 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan
| | - Taku Fukuzawa
- Department of Life Science and Technology, Tokyo Institute of Technology, 4259-B13 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan
| | - Ryotaro Demizu
- Department of Life Science and Technology, Tokyo Institute of Technology, 4259-B13 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan
| | - Tomoya Sato
- Department of Life Science and Technology, Tokyo Institute of Technology, 4259-B13 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan
| | - Rahmaningsih Mara Sabirin
- Department of Life Science and Technology, Tokyo Institute of Technology, 4259-B13 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan.,Department of Physiology, Faculty of Medicine, Public Health and Nursing, Gadjah Mada University, JI.Farmako Sekip Utara, Yogyakarta, 55281, Indonesia
| | - Shigehisa Hirose
- Department of Life Science and Technology, Tokyo Institute of Technology, 4259-B13 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan
| | - Nobuhiro Nakamura
- Department of Life Science and Technology, Tokyo Institute of Technology, 4259-B13 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan.
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