scholarly journals PRMT7 targets of Foxm1 controls alveolar myofibroblast proliferation and differentiation during alveologenesis

2021 ◽  
Vol 12 (9) ◽  
Author(s):  
Huacheng He ◽  
Jilin Chen ◽  
Jian Zhao ◽  
Peizhun Zhang ◽  
Yulong Qiao ◽  
...  
Keyword(s):  
Epigenetic Mechanism ◽  
Chronic Obstructive ◽  
Histone H4 ◽  
Obstructive Pulmonary Disease ◽  
Forkhead Box ◽  
Forkhead Box M1 ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Direct Target ◽  
Deficient Mice

AbstractAlthough aberrant alveolar myofibroblasts (AMYFs) proliferation and differentiation are often associated with abnormal lung development and diseases, such as bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF), epigenetic mechanisms regulating proliferation and differentiation of AMYFs remain poorly understood. Protein arginine methyltransferase 7 (PRMT7) is the only reported type III enzyme responsible for monomethylation of arginine residue on both histone and nonhistone substrates. Here we provide evidence for PRMT7’s function in regulating AMYFs proliferation and differentiation during lung alveologenesis. In PRMT7-deficient mice, we found reduced AMYFs proliferation and differentiation, abnormal elastin deposition, and failure of alveolar septum formation. We further shown that oncogene forkhead box M1 (Foxm1) is a direct target of PRMT7 and that PRMT7-catalyzed monomethylation at histone H4 arginine 3 (H4R3me1) directly associate with chromatin of Foxm1 to activate its transcription, and thereby regulate of cell cycle-related genes to inhibit AMYFs proliferation and differentiation. Overexpression of Foxm1 in isolated myofibroblasts (MYFs) significantly rescued PRMT7-deficiency-induced cell proliferation and differentiation defects. Thus, our results reveal a novel epigenetic mechanism through which PRMT7-mediated histone arginine monomethylation activates Foxm1 transcriptional expression to regulate AMYFs proliferation and differentiation during lung alveologenesis and may represent a potential target for intervention in pulmonary diseases.

scholarly journals Upregulation of Leukocyte Immunoglobulin-Like Receptor B4 on Interstitial Macrophages in COPD; Their Possible Protective Role Against Emphysema Formation

2021 ◽  
Author(s):  
Ayumi Mitsune ◽  
Mitsuhiro Yamada ◽  
Naoya Fujino ◽  
Tadahisa Numakura ◽  
Tomohiro Ichikawa ◽  
...  
Keyword(s):  
Mouse Model ◽  
Inflammatory Responses ◽  
Feedback System ◽  
Surface Expression ◽  
Protective Role ◽  
Chronic Obstructive ◽  
Wild Type ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients ◽  
Deficient Mice

Abstract Background: Leukocyte immunoglobulin-like receptor B4 (LILRB4) is one of the inhibitory receptors in various types of immune cells including macrophages. Previous reports suggested that LILRB4 could be involved in a negative feedback system to prevent excessive inflammatory responses. However, its role has been unclear in chronic obstructive pulmonary disease (COPD), in which macrophages play a crucial role in the pathogenesis. In this study, we aimed to examine the changes of LILRB4 on macrophages both in the lung specimens of COPD patients and the lungs of a mouse emphysema model. We then tried to compare the differences in both inflammation and emphysematous changes of the model between wild-type and LILRB4-deficient mice in order to elucidate the role of LILRB4 in the pathogenesis of COPD.Methods: We prepared single-cell suspensions of resected lung specimens of never-smokers (n = 21), non-COPD smokers (n = 16), and COPD patients (n = 14). The identification of LILRB4-expressing cells and the level of LILRB4 expression were evaluated by flow cytometry. We analyzed the relationships between the LILRB4 expression and clinical characteristics including respiratory function. In the experiments using an elastase-induced mouse model of emphysema, we also analyzed the LILRB4 expression on lung macrophages. We compared inflammatory cell accumulation and emphysematous changes induced by elastase instillation between wild-type and LILRB4-deficient mice.Results: The levels of surface expression of LILRB4 are relatively high on monocyte linage cells including macrophages in the human lungs. The percentage of LILRB4+ cells in lung interstitial macrophages was increased in COPD patients compared to non-COPD smokers (p = 0.018) and correlated with the severity of emphysematous lesions detected by CT scan (rs = 0.559, p < 0.001), whereas the amount of smoking showed no correlation with LILRB4 expression. Increased LILRB4 on interstitial macrophages was also observed in elastase-treated mice (p = 0.008). LILRB4-deficient mice showed severer emphysematous lesions with increased MMP-12 expression in the model.Conclusions: LILRB4 on interstitial macrophages was upregulated both in human COPD lungs and in a mouse model of emphysema. This upregulated LILRB4 may have a protective effect against emphysema formation, possibly through decreasing MMP-12 expression in the lungs.

scholarly journals TLR7 promotes smoke-induced lung damage through the activity of mast cell tryptase

2020 ◽  
Author(s):  
Tatt Jhong Haw ◽  
Malcolm Starkey ◽  
Stelios Pavlidis ◽  
Sheena Tam ◽  
Prema M. Nair ◽  
...  
Keyword(s):  
Mast Cell ◽  
Cell Activity ◽  
Lung Damage ◽  
Chronic Obstructive ◽  
Toll Like Receptor ◽  
Mast Cell Tryptase ◽  
Obstructive Pulmonary Disease ◽  
Mast Cell Stabilizer ◽  
Tlr7 Agonist ◽  
Deficient Mice

Abstract Toll-like receptor (TLR)7 is known for eliciting immunity against single-stranded RNA viruses. TLR7 was increased in both human and cigarette smoke (CS)-induced experimental chronic obstructive pulmonary disease (COPD). Severity of CS-induced emphysema and COPD was reduced in TLR7-deficient mice whilst inhalation of imiquimod (TLR7-agonist) induced emphysema in naïve mice. Imiquimod-induced emphysema was reduced in mice treated with mast cell stabilizer cromolyn or deficient in mast cell protease-6. Therapeutic treatment with anti-TLR7 monoclonal antibody suppressed CS-induced emphysema, experimental COPD and accumulation of pulmonary mast cells. We demonstrate an unexpected role for TLR7 in mediating emphysema and COPD through mast cell activity.

scholarly journals Airway Wall Remodeling in Childhood Asthma—A Personalized Perspective from Cell Type-Specific Biology

2021 ◽  
Vol 11 (11) ◽  
pp. 1229
Author(s):  
Lei Fang ◽  
Michael Roth
Keyword(s):  
Childhood Asthma ◽  
Lung Diseases ◽  
Structural Changes ◽  
Bronchial Epithelium ◽  
Cell Interaction ◽  
Epigenetic Mechanism ◽  
Chronic Obstructive ◽  
Airway Wall ◽  
Obstructive Pulmonary Disease ◽  
Cell Type Specific

Airway wall remodeling is a pathology occurring in chronic inflammatory lung diseases including asthma, chronic obstructive pulmonary disease, and fibrosis. In 2017, the American Thoracic Society released a research statement highlighting the gaps in knowledge and understanding of airway wall remodeling. The four major challenges addressed in this statement were: (i) the lack of consensus to define “airway wall remodeling” in different diseases, (ii) methodologic limitations and inappropriate models, (iii) the lack of anti-remodeling therapies, and (iv) the difficulty to define endpoints and outcomes in relevant studies. This review focuses on the importance of cell-cell interaction, especially the bronchial epithelium, in asthma-associated airway wall remodeling. The pathology of “airway wall remodeling” summarizes all structural changes of the airway wall without differentiating between different pheno- or endo-types of asthma. Indicators of airway wall remodeling have been reported in childhood asthma in the absence of any sign of inflammation; thus, the initiation event remains unknown. Recent studies have implied that the interaction between the epithelium with immune cells and sub-epithelial mesenchymal cells is modified in asthma by a yet unknown epigenetic mechanism during early childhood.

Foxl1-deficient mice exhibit aberrant epithelial cell positioning resulting from dysregulated EphB/EphrinB expression in the small intestine

2006 ◽  
Vol 291 (1) ◽  
pp. G163-G170 ◽  
Author(s):  
Masumi Takano-Maruyama ◽  
Koji Hase ◽  
Hiroshi Fukamachi ◽  
Yasutaka Kato ◽  
Haruhiko Koseki ◽  
...  
Keyword(s):  
Small Intestine ◽  
Epithelial Cell ◽  
Paneth Cell ◽  
Real Time Quantitative Pcr ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Cell Positioning ◽  
Winged Helix Transcription Factor ◽  
Deficient Mice

The winged helix transcription factor Foxl1, expressed in the gut mesenchyme, regulates epithelial cell proliferation and differentiation through the Wnt/β-catenin pathway. To better understand the role of Foxl1 in epithelial morphogenesis, we examined the tissue structure and positioning of epithelial cells in the small intestine of Foxl1-deficient mice. The small intestine of Foxl1-deficient mice manifested aberrant crypt structure, including widely distributed Paneth cells, which coincided with the ectopic and increased expression of EphB2 and EphB3, which are key regulators of epithelial cell positioning. Furthermore, real-time quantitative PCR indicated that a subset of Wnt family genes was highly expressed in the gut mesenchyme of Foxl1-deficient mice compared with that of wild-type mice. Such an increase in Wnt expression was remarkable in the mesenchyme, where the aberrant Paneth cell positioning was observed by in situ hybridization. Foxl1 plays an important role in the maintenance of crypt architecture and epithelial cell positioning through the mesenchymal-epithelial interaction in the small intestine. This interaction is essential for the normal regulation of the Wnt/β-catenin pathway and the subsequent EphB/EphrinB expression.

scholarly journals p300/Sp1-Mediated High Expression of p16 Promotes Endothelial Progenitor Cell Senescence Leading to the Occurrence of Chronic Obstructive Pulmonary Disease

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Zhihui He ◽  
Huaihuai Peng ◽  
Min Gao ◽  
Guibin Liang ◽  
Menghao Zeng ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Peripheral Blood ◽  
Promoter Region ◽  
High Expression ◽  
Chronic Obstructive ◽  
Histone H4 ◽  
Obstructive Pulmonary Disease ◽  
Acetylation Level ◽  
Copd Patients ◽  
Histone H4 Acetylation

Objective. Chronic obstructive pulmonary disease (COPD) is a common chronic disease and develops rapidly into a grave public health problem worldwide. However, what exactly causes the occurrence of COPD remains largely unclear. Here, we are trying to explore whether the high expression of p16 mediated by p300/Sp1 can cause chronic obstructive pulmonary disease through promoting the senescence of endothelial progenitor cells (EPCs). Methods. Peripheral blood EPCs were isolated from nonsmoking non-COPD, smoking non-COPD, and smoking COPD patients. The expressions of p16, p300, and senescence-related genes were detected by RT-PCR and Western Blot. Then, we knocked down or overexpressed Sp1 and p300 and used the ChIP assay to detect the histone H4 acetylation level in the promoter region of p16, CCK8 to detect cell proliferation, flow cytometry to detect the cell cycle, and β-galactosidase staining to count the proportion of senescent cells. Results. The high expression of p16 was found in peripheral blood EPCs of COPD patients; the cigarette smoke extract (CSE) led to the increase of p16. The high expression of p16 in EPCs promoted cell cycle arrest and apoptosis. The CSE-mediated high expression of p16 promoted cell senescence. The expression of p300 was increased in peripheral blood EPCs of COPD patients. Moreover, p300/Sp1 enhanced the histone H4 acetylation level in the promoter region of p16, thereby mediating the senescence of EPCs. And knockdown of p300/Sp1 could rescue CSE-mediated cell senescence. Conclusion. p300/Sp1 enhanced the histone H4 acetylation level in the p16 promoter region to mediate the senescence of EPCs.

scholarly journals Harnessing the ECM Microenvironment to Ameliorate Mesenchymal Stromal Cell-Based Therapy in Chronic Lung Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Linda Elowsson Rendin ◽  
Anna Löfdahl ◽  
Måns Kadefors ◽  
Zackarias Söderlund ◽  
Emil Tykesson ◽  
...  
Keyword(s):  
Lung Diseases ◽  
Biomechanical Properties ◽  
Chronic Obstructive ◽  
Tissue Remodelling ◽  
Tissue Slices ◽  
Obstructive Pulmonary Disease ◽  
Cell Responses ◽  
Cell Based Therapy ◽  
Chronic Lung Diseases ◽  
Proliferation And Differentiation

It is known that the cell environment such as biomechanical properties and extracellular matrix (ECM) composition dictate cell behaviour including migration, proliferation, and differentiation. Important constituents of the microenvironment, including ECM molecules such as proteoglycans and glycosaminoglycans (GAGs), determine events in both embryogenesis and repair of the adult lung. Mesenchymal stromal/stem cells (MSC) have been shown to have immunomodulatory properties and may be potent actors regulating tissue remodelling and regenerative cell responses upon lung injury. Using MSC in cell-based therapy holds promise for treatment of chronic lung diseases such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). However, so far clinical trials with MSCs in COPD have not had a significant impact on disease amelioration nor on IPF, where low cell survival rate and pulmonary retention time are major hurdles to overcome. Research shows that the microenvironment has a profound impact on transplanted MSCs. In our studies on acellular lung tissue slices (lung scaffolds) from IPF patients versus healthy individuals, we see a profound effect on cellular activity, where healthy cells cultured in diseased lung scaffolds adapt and produce proteins further promoting a diseased environment, whereas cells on healthy scaffolds sustain a healthy proteomic profile. Therefore, modulating the environmental context for cell-based therapy may be a potent way to improve treatment using MSCs. In this review, we will describe the importance of the microenvironment for cell-based therapy in chronic lung diseases, how MSC-ECM interactions can affect therapeutic output and describe current progress in the field of cell-based therapy.

Impaired B-cell development at the pre-BII-cell stage in galectin-1–deficient mice due to inefficient pre-BII/stromal cell interactions

Blood ◽  
2009 ◽  
Vol 113 (23) ◽  
pp. 5878-5886 ◽  
Author(s):  
Marion Espeli ◽  
Stéphane J. C. Mancini ◽  
Caroline Breton ◽  
Françoise Poirier ◽  
Claudine Schiff
Keyword(s):  
Bone Marrow ◽  
Cell Proliferation ◽  
Cell Differentiation ◽  
B Cell ◽  
Stromal Cell ◽  
Cell Phenotype ◽  
Cell Proliferation And Differentiation ◽  
Hydroxyurea Treatment ◽  
Proliferation And Differentiation ◽  
Deficient Mice

Abstract Activation of the pre-B-cell receptor (pre-BCR) in the bone marrow depends on both tonic and ligand-induced signaling and leads to pre-BII-cell proliferation and differentiation. Using normal mouse bone marrow pre-BII cells, we demonstrate that the ligand-induced pre-BCR activation depends on pre-BCR/galectin-1/integrin interactions leading to pre-BCR clustering at the pre-BII/stromal cell synapse. In contrast, heparan sulfates, shown to be pre-BCR ligands in mice, are not implicated in pre-BCR relocalization. Inhibition of pre-BCR/galectin-1/integrin interactions has functional consequences, since pre-BII-cell proliferation and differentiation are impaired in an in vitro B-cell differentiation assay, without affecting cellular apoptosis. Most strikingly, although galectin-1–deficient mice do not show an apparent B-cell phenotype, the kinetics of de novo B-cell reconstitution after hydroxyurea treatment indicates a specific delay in pre-BII-cell recovery due to a decrease in pre-BII-cell differentiation and proliferation. Thus, although it remains possible that the pre-BCR interacts with other ligands, these results highlight the role played by the stromal cell–derived galectin-1 for the efficient development of normal pre-BII cells and suggest the existence of pre-BII–specific stromal cell niches in normal bone marrow.

Hyperoxia increases leptin production: a mechanism mediated through endogenous elevation of corticosterone

2001 ◽  
Vol 281 (5) ◽  
pp. L1150-L1156 ◽  
Author(s):  
Constance Barazzone-Argiroffo ◽  
Patrick Muzzin ◽  
Yves R. Donati ◽  
Chen-Da Kan ◽  
Michel L. Aubert ◽  
...  
Keyword(s):  
Weight Loss ◽  
Lung Damage ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Oxygen Breathing ◽  
Factor Α ◽  
Deficient Mice ◽  
Necrosis Factor ◽  
Alveolar Edema

Leptin, a cytokine involved in the regulation of food intake, has been reported to be decreased in lung diseases such as chronic obstructive pulmonary disease and cystic fibrosis and increased in critically ill patients with sepsis. We investigated the role of leptin during hyperoxia in mice, which results in alveolar edema, severe weight loss, and death within 3–4 days. In oxygen-breathing mice, serum leptin was increased six- to sevenfold and its mRNA was upregulated in white adipose tissue. Leptin elevation could not be attributed to changes in circulating tumor necrosis factor-α but was completely dependent on endogenous corticosterone elevation because adrenalectomized mice did not exhibit any increase in leptin levels. Using leptin-deficient mice and wild-type mice treated with anti-leptin antibody, we demonstrate that weight loss was leptin independent. Lung damage was moderately attenuated in leptin-deficient mice but was not modified by anti-leptin antibody or leptin administration, suggesting that leptin does not play an essential role in the direct and short-term effects of oxygen-induced injury.

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