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1.
Immunity ; 56(1): 78-92.e6, 2023 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-36630919

RESUMO

Tissue repair processes maintain proper organ function following mechanical or infection-related damage. In addition to antibacterial properties, mucosal associated invariant T (MAIT) cells express a tissue repair transcriptomic program and promote skin wound healing when expanded. Herein, we use a human-like mouse model of full-thickness skin excision to assess the underlying mechanisms of MAIT cell tissue repair function. Single-cell RNA sequencing analysis suggested that skin MAIT cells already express a repair program at steady state. Following skin excision, MAIT cells promoted keratinocyte proliferation, thereby accelerating healing. Using skin grafts, parabiosis, and adoptive transfer experiments, we show that MAIT cells migrated into the wound in a T cell receptor (TCR)-independent but CXCR6 chemokine receptor-dependent manner. Amphiregulin secreted by MAIT cells following excision promoted wound healing. Expression of the repair function was probably independent of sustained TCR stimulation. Overall, our study provides mechanistic insights into MAIT cell wound healing function in the skin.


Assuntos
Anfirregulina , Antígenos de Histocompatibilidade Classe I , Células T Invariantes Associadas à Mucosa , Cicatrização , Animais , Humanos , Camundongos , Anfirregulina/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Menor , Células T Invariantes Associadas à Mucosa/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo
2.
Cell ; 168(6): 1101-1113.e13, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28283064

RESUMO

We molecularly dissected leptomeningeal metastasis, or spread of cancer to the cerebrospinal fluid (CSF), which is a frequent and fatal condition mediated by unknown mechanisms. We selected lung and breast cancer cell lines for the ability to infiltrate and grow in CSF, a remarkably acellular, mitogen-poor metastasis microenvironment. Complement component 3 (C3) was upregulated in four leptomeningeal metastatic models and proved necessary for cancer growth within the leptomeningeal space. In human disease, cancer cells within the CSF produced C3 in correlation with clinical course. C3 expression in primary tumors was predictive of leptomeningeal relapse. Mechanistically, we found that cancer-cell-derived C3 activates the C3a receptor in the choroid plexus epithelium to disrupt the blood-CSF barrier. This effect allows plasma components, including amphiregulin, and other mitogens to enter the CSF and promote cancer cell growth. Pharmacologic interference with C3 signaling proved therapeutically beneficial in suppressing leptomeningeal metastasis in these preclinical models.


Assuntos
Complemento C3/metabolismo , Neoplasias Meníngeas/secundário , Metástase Neoplásica/patologia , Animais , Neoplasias da Mama/patologia , Líquido Cefalorraquidiano , Plexo Corióideo/irrigação sanguínea , Complemento C3/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias Pulmonares/patologia , Antígeno de Macrófago 1/metabolismo , Camundongos , Transdução de Sinais , Microambiente Tumoral , Regulação para Cima
3.
Immunity ; 55(5): 895-911.e10, 2022 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-35483356

RESUMO

Different effector arms of the immune system are optimized to protect from different classes of pathogens. In some cases, pathogens manipulate the host immune system to promote the wrong type of effector response-a phenomenon known as immune deviation. Typically, immune deviation helps pathogens to avoid destructive immune responses. Here, we report on a type of immune deviation whereby an opportunistic pathogen, Pseudomonas aeruginosa (P. aeruginosa), induces the type 2 immune response resulting in mucin production that is used as an energy source by the pathogen. Specifically, P. aeruginosa-secreted toxin, LasB, processed and activated epithelial amphiregulin to induce type 2 inflammation and mucin production. This "niche remodeling" by P. aeruginosa promoted colonization and, as a by-product, allergic sensitization. Our study thus reveals a type of bacterial immune deviation by increasing nutrient supply. It also uncovers a mechanism of allergic sensitization by a bacterial virulence factor.


Assuntos
Infecções por Pseudomonas , Pseudomonas aeruginosa , Proteínas de Bactérias , Humanos , Inflamação , Mucinas
4.
Immunity ; 54(6): 1186-1199.e7, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-33915108

RESUMO

A cardinal feature of COVID-19 is lung inflammation and respiratory failure. In a prospective multi-country cohort of COVID-19 patients, we found that increased Notch4 expression on circulating regulatory T (Treg) cells was associated with disease severity, predicted mortality, and declined upon recovery. Deletion of Notch4 in Treg cells or therapy with anti-Notch4 antibodies in conventional and humanized mice normalized the dysregulated innate immunity and rescued disease morbidity and mortality induced by a synthetic analog of viral RNA or by influenza H1N1 virus. Mechanistically, Notch4 suppressed the induction by interleukin-18 of amphiregulin, a cytokine necessary for tissue repair. Protection by Notch4 inhibition was recapitulated by therapy with Amphiregulin and, reciprocally, abrogated by its antagonism. Amphiregulin declined in COVID-19 subjects as a function of disease severity and Notch4 expression. Thus, Notch4 expression on Treg cells dynamically restrains amphiregulin-dependent tissue repair to promote severe lung inflammation, with therapeutic implications for COVID-19 and related infections.


Assuntos
Interações Hospedeiro-Patógeno , Imunidade Celular , Pneumonia Viral/etiologia , Pneumonia Viral/metabolismo , Receptor Notch4/metabolismo , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Anfirregulina/farmacologia , Animais , Biomarcadores , Citocinas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imuno-Histoquímica , Imunomodulação/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Vírus da Influenza A/fisiologia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Camundongos , Camundongos Transgênicos , Pneumonia Viral/patologia , Receptor Notch4/antagonistas & inibidores , Receptor Notch4/genética , Índice de Gravidade de Doença
5.
Immunity ; 50(3): 645-654.e6, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30770250

RESUMO

The epidermal growth factor receptor ligand Amphiregulin has a well-documented role in the restoration of tissue homeostasis after injury; however, the mechanism by which Amphiregulin contributes to wound repair remains unknown. Here we show that Amphiregulin functioned by releasing bioactive transforming growth factor beta (TGF-ß) from latent complexes via integrin-αV activation. Using acute injury models in two different tissues, we found that by inducing TGF-ß activation on mesenchymal stromal cells (pericytes), Amphiregulin induced their differentiation into myofibroblasts, thereby selectively contributing to the restoration of vascular barrier function within injured tissue. Furthermore, we identified macrophages as a critical source of Amphiregulin, revealing a direct effector mechanism by which these cells contribute to tissue restoration after acute injury. Combined, these observations expose a so far under-appreciated mechanism of how cells of the immune system selectively control the differentiation of tissue progenitor cells during tissue repair and inflammation.


Assuntos
Anfirregulina/metabolismo , Macrófagos/metabolismo , Pericitos/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Diferenciação Celular/fisiologia , Feminino , Masculino , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Miofibroblastos/metabolismo
6.
EMBO J ; 42(16): e114153, 2023 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-37382276

RESUMO

Innate lymphoid cells (ILCs) are a diverse population of cells that include NK cells and contribute to tissue homeostasis and repair, inflammation, and provide protection from infection. The interplay between human blood ILCs, as well as their responses to HIV-1 infection, remains poorly understood. This study used transcriptional and chromatin profiling to explore these questions. Transcriptional profiling and flow cytometry analysis support that there are four main ILC subsets found in human blood. Unlike in mice, human NK cells expressed the tissue repair protein amphiregulin (AREG). AREG production was induced by TCF7/WNT, IL-2, and IL-15, and inhibited by TGFB1, a cytokine increased in people living with HIV-1. In HIV-1 infection, the percentage of AREG+ NK cells correlated positively with the numbers of ILCs and CD4+ T cells but negatively with the concentration of inflammatory cytokine IL-6. NK-cell knockout of the TGFB1-stimulated WNT antagonist RUNX3 increased AREG production. Antiviral gene expression was increased in all ILC subsets from HIV-1 viremic people, and anti-inflammatory gene MYDGF was increased in an NK-cell subset from HIV-1-infected people whose viral load was undetectable in the absence of antiretroviral therapy. The percentage of defective NK cells in people living with HIV-1 correlated inversely with ILC percentage and CD4+ T-cell counts. CD4+ T cells and their production of IL-2 prevented the loss of NK-cell function by activating mTOR. These studies clarify how ILC subsets are interrelated and provide insight into how HIV-1 infection disrupts NK cells, including an uncharacterized homeostatic function in NK cells.


Assuntos
Infecções por HIV , HIV-1 , Humanos , Camundongos , Animais , Imunidade Inata , Linfócitos/metabolismo , HIV-1/metabolismo , Interleucina-2/metabolismo , Cromatina , Células Matadoras Naturais , Citocinas , Infecções por HIV/genética
7.
Immunity ; 49(1): 134-150.e6, 2018 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-29958800

RESUMO

Memory T cells provide long-lasting protective immunity, and distinct subpopulations of memory T cells drive chronic inflammatory diseases such as asthma. Asthma is a chronic allergic inflammatory disease with airway remodeling including fibrotic changes. The immunological mechanisms that induce airway fibrotic changes remain unknown. We found that interleukin-33 (IL-33) enhanced amphiregulin production by the IL-33 receptor, ST2hi memory T helper 2 (Th2) cells. Amphiregulin-epidermal growth factor receptor (EGFR)-mediated signaling directly reprogramed eosinophils to an inflammatory state with enhanced production of osteopontin, a key profibrotic immunomodulatory protein. IL-5-producing memory Th2 cells and amphiregulin-producing memory Th2 cells appeared to cooperate to establish lung fibrosis. The analysis of polyps from patients with eosinophilic chronic rhinosinusitis revealed fibrosis with accumulation of amphiregulin-producing CRTH2hiCD161hiCD45RO+CD4+ Th2 cells and osteopontin-producing eosinophils. Thus, the IL-33-amphiregulin-osteopontin axis directs fibrotic responses in eosinophilic airway inflammation and is a potential target for the treatment of fibrosis induced by chronic allergic disorders.


Assuntos
Anfirregulina/imunologia , Eosinófilos/imunologia , Osteopontina/metabolismo , Fibrose Pulmonar/imunologia , Transdução de Sinais/imunologia , Células Th2/imunologia , Anfirregulina/biossíntese , Anfirregulina/metabolismo , Anfirregulina/farmacologia , Animais , Modelos Animais de Doenças , Receptores ErbB/metabolismo , Feminino , Memória Imunológica/imunologia , Imunomodulação , Interleucina-33/metabolismo , Camundongos , Rinite/imunologia , Rinite/patologia , Sinusite/imunologia , Sinusite/patologia , Transcrição Gênica/efeitos dos fármacos
8.
Immunity ; 49(3): 531-544.e6, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30170813

RESUMO

Compared to adults, infants suffer higher rates of hospitalization, severe clinical complications, and mortality due to influenza infection. We found that γδ T cells protected neonatal mice against mortality during influenza infection. γδ T cell deficiency did not alter viral clearance or interferon-γ production. Instead, neonatal influenza infection induced the accumulation of interleukin-17A (IL-17A)-producing γδ T cells, which was associated with IL-33 production by lung epithelial cells. Neonates lacking IL-17A-expressing γδ T cells or Il33 had higher mortality upon influenza infection. γδ T cells and IL-33 promoted lung infiltration of group 2 innate lymphoid cells and regulatory T cells, resulting in increased amphiregulin secretion and tissue repair. In influenza-infected children, IL-17A, IL-33, and amphiregulin expression were correlated, and increased IL-17A levels in nasal aspirates were associated with better clinical outcomes. Our results indicate that γδ T cells are required in influenza-infected neonates to initiate protective immunity and mediate lung homeostasis.


Assuntos
Vírus da Influenza A/fisiologia , Influenza Humana/imunologia , Interleucina-17/metabolismo , Pulmão/imunologia , Infecções por Orthomyxoviridae/imunologia , Linfócitos T/imunologia , Células Th2/imunologia , Adulto , Anfirregulina/metabolismo , Animais , Células Cultivadas , Criança , Humanos , Imunidade , Recém-Nascido , Interleucina-33/metabolismo , Camundongos , Prognóstico , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo
9.
J Cell Sci ; 136(13)2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-37282854

RESUMO

Tylosis with oesophageal cancer (TOC) is a rare familial disorder caused by cytoplasmic mutations in inactive rhomboid 2 (iRhom2 or iR2, encoded by Rhbdf2). iR2 and the related iRhom1 (or iR1, encoded by Rhbdf1) are key regulators of the membrane-anchored metalloprotease ADAM17, which is required for activating EGFR ligands and for releasing pro-inflammatory cytokines such as TNFα (or TNF). A cytoplasmic deletion in iR2, including the TOC site, leads to curly coat or bare skin (cub) in mice, whereas a knock-in TOC mutation (toc) causes less severe alopecia and wavy fur. The abnormal skin and hair phenotypes of iR2cub/cub and iR2toc/toc mice depend on amphiregulin (Areg) and Adam17, as loss of one allele of either gene rescues the fur phenotypes. Remarkably, we found that iR1-/- iR2cub/cub mice survived, despite a lack of mature ADAM17, whereas iR2cub/cub Adam17-/- mice died perinatally, suggesting that the iR2cub gain-of-function mutation requires the presence of ADAM17, but not its catalytic activity. The iR2toc mutation did not substantially reduce the levels of mature ADAM17, but instead affected its function in a substrate-selective manner. Our findings provide new insights into the role of the cytoplasmic domain of iR2 in vivo, with implications for the treatment of TOC patients.


Assuntos
Ceratodermia Palmar e Plantar Difusa , Ceratodermia Palmar e Plantar , Neoplasias , Animais , Camundongos , Proteína ADAM17/genética , Proteína ADAM17/metabolismo , Proteínas de Transporte/genética , Ceratodermia Palmar e Plantar/genética , Proteínas de Membrana/genética
10.
Gastroenterology ; 167(3): 469-484, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38492892

RESUMO

BACKGROUND & AIMS: Isthmic progenitors, tissue-specific stem cells in the stomach corpus, maintain mucosal homeostasis by balancing between proliferation and differentiation to gastric epithelial lineages. The progenitor cells rapidly adopt an active state in response to mucosal injury. However, it remains unclear how the isthmic progenitor cell niche is controlled during the regeneration of damaged epithelium. METHODS: We recapitulated tissue recovery process after acute mucosal injury in the mouse stomach. Bromodeoxyuridine incorporation was used to trace newly generated cells during the injury and recovery phases. To define the epithelial lineage commitment process during recovery, we performed single-cell RNA-sequencing on epithelial cells from the mouse stomachs. We validated the effects of amphiregulin (AREG) on mucosal recovery, using recombinant AREG treatment or AREG-deficient mice. RESULTS: We determined that an epidermal growth factor receptor ligand, AREG, can control progenitor cell lineage commitment. Based on the identification of lineage-committed subpopulations in the corpus epithelium through single-cell RNA-sequencing and bromodeoxyuridine incorporation, we showed that isthmic progenitors mainly transition into short-lived surface cell lineages but are less frequently committed to long-lived parietal cell lineages in homeostasis. However, mucosal regeneration after damage directs the lineage commitment of isthmic progenitors towards parietal cell lineages. During recovery, AREG treatment promoted repopulation with parietal cells, while suppressing surface cell commitment of progenitors. In contrast, transforming growth factor-α did not alter parietal cell regeneration, but did induce expansion of surface cell populations. AREG deficiency impairs parietal cell regeneration but increases surface cell commitment. CONCLUSIONS: These data demonstrate that different epidermal growth factor receptor ligands can distinctly regulate isthmic progenitor-driven mucosal regeneration and lineage commitment.


Assuntos
Anfirregulina , Diferenciação Celular , Linhagem da Célula , Mucosa Gástrica , Regeneração , Células-Tronco , Anfirregulina/metabolismo , Anfirregulina/genética , Animais , Mucosa Gástrica/citologia , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Células-Tronco/metabolismo , Camundongos , Proliferação de Células , Células Epiteliais/metabolismo , Receptores ErbB/metabolismo , Receptores ErbB/genética , Camundongos Knockout , Transdução de Sinais , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Análise de Célula Única , Masculino
11.
FASEB J ; 38(4): e23488, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38358359

RESUMO

Myocardial infarction (MI) is defined as sudden ischemic death of myocardial tissue. Amphiregulin (Areg) regulates cell survival and is crucial for the healing of tissues after damage. However, the functions and mechanisms of Areg after MI remain unclear. Here, we aimed to investigate Areg's impact on myocardial remodeling. Mice model of MI was constructed and Areg-/- mice were used. Expression of Areg was analyzed using western blotting, RT-qPCR, flow cytometry, and immunofluorescence staining. Echocardiographic analysis, Masson's trichrome, and triphenyltetrazolium chloride staining were used to assess cardiac function and structure. RNA sequencing was used for unbiased analysis. Apoptosis and autophagy were determined by western blotting, TUNEL staining, electron microscopy, and mRFP-GFP-LC3 lentivirus. Lysosomal acidity was determined by Lysotracker staining. Areg was elevated in the infarct border zone after MI. It was mostly secreted by macrophages. Areg deficiency aggravated adverse ventricular remodeling, as reflected by worsening cardiac function, a lower survival rate, increased scar size, and interstitial fibrosis. RNA sequencing analyses showed that Areg related to the epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase/protein kinase B (PI3K-Akt), mammalian target of rapamycin (mTOR) signaling pathways, V-ATPase and lysosome pathways. Mechanistically, Areg exerts beneficial effects via increasing lysosomal acidity to promote autophagosome clearance, and activating the EGFR/PI3K/Akt/mTOR signaling pathway, subsequently inhibiting excessive autophagosome formation and apoptosis in cardiomyocytes. This study provides a novel evidence for the role of Areg in inhibiting ventricular remodeling after MI by regulating autophagy and apoptosis and identifies Areg as a potential therapeutic target in ventricular remodeling after MI.


Assuntos
Infarto do Miocárdio , Fosfatidilinositol 3-Quinases , Animais , Camundongos , Anfirregulina/genética , Apoptose , Autofagia , Receptores ErbB , Mamíferos , Proteínas Proto-Oncogênicas c-akt , Serina-Treonina Quinases TOR , Remodelação Ventricular
12.
J Allergy Clin Immunol ; 153(4): 1095-1112, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38092138

RESUMO

BACKGROUND: IgG4-related disease (IgG4-RD), an example of a type I immune disease, is an immune-mediated fibrotic disorder characterized by dysregulated resolution of severe inflammation and wound healing. However, truly dominant or pathognomonic autoantibodies related to IgG4-RD are not identified. OBJECTIVE: We sought to perform single-cell RNA sequencing and T-cell receptor and B-cell receptor sequencing to obtain a comprehensive, unbiased view of tissue-infiltrating T and B cells. METHODS: We performed unbiased single-cell RNA-sequencing analysis for the transcriptome and T-cell receptor sequencing and B-cell receptor sequencing on sorted CD3+ T or CD19+ B cells from affected tissues of patients with IgG4-RD. We also conducted quantitative analyses of CD3+ T-cell and CD19+ B-cell subsets in 68 patients with IgG4-RD and 30 patients with Sjögren syndrome. RESULTS: Almost all clonally expanded T cells in these lesions were either Granzyme K (GZMK)-expressing CD4+ cytotoxic T cells or GZMK+CD8+ T cells. These GZMK-expressing cytotoxic T cells also expressed amphiregulin and TGF-ß but did not express immune checkpoints, and the tissue-infiltrating CD8+ T cells were phenotypically heterogeneous. MKI67+ B cells and IgD-CD27-CD11c-CXCR5- double-negative 3 B cells were clonally expanded and infiltrated affected tissue lesions. GZMK+CD4+ cytotoxic T cells colocalized with MKI67+ B cells in the extrafollicular area from affected tissue sites. CONCLUSIONS: The above-mentioned cells likely participate in T-B collaborative events, suggesting possible avenues for targeted therapies. Our findings were validated using orthogonal approaches, including multicolor immunofluorescence and the use of comparator disease groups, to support the central role of cytotoxic CD4+ and CD8+ T cells expressing GZMK, amphiregulin, and TGF-ß in the pathogenesis of inflammatory fibrotic disorders.


Assuntos
Doenças do Sistema Imunitário , Doença Relacionada a Imunoglobulina G4 , Humanos , Anfirregulina/genética , Linfócitos T CD8-Positivos , Granzimas , Receptores de Antígenos de Linfócitos B , Receptores de Antígenos de Linfócitos T , Linfócitos T Citotóxicos , Fator de Crescimento Transformador beta
13.
Rheumatology (Oxford) ; 63(3): 837-845, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-37310903

RESUMO

OBJECTIVE: Multiple observations indicate a role for lymphocytes in driving autoimmunity in SSc. While T and NK cells have been studied in SSc whole blood and bronchoalveolar lavage fluid, their role remains unclear, partly because no studies have analysed these cell types in SSc-interstitial lung disease (ILD) lung tissue. This research aimed to identify and analyse the lymphoid subpopulations in SSc-ILD lung explants. METHODS: Lymphoid populations from 13 SSc-ILD and 6 healthy control (HC) lung explants were analysed using Seurat following single-cell RNA sequencing. Lymphoid clusters were identified by their differential gene expression. Absolute cell numbers and cell proportions in each cluster were compared between cohorts. Additional analyses were performed using pathway analysis, pseudotime and cell ligand-receptor interactions. RESULTS: Activated CD16+ NK cells, CD8+ tissue resident memory T cells and Treg cells were proportionately higher in SSc-ILD compared with HC lungs. Activated CD16+ NK cells in SSc-ILD showed upregulated granzyme B, IFN-γ and CD226. Amphiregulin, highly upregulated by NK cells, was predicted to interact with epidermal growth factor receptor on several bronchial epithelial cell populations. Shifts in CD8+ T cell populations indicated a transition from resting to effector to tissue resident phenotypes in SSc-ILD. CONCLUSIONS: SSc-ILD lungs show activated lymphoid populations. Activated cytotoxic NK cells suggest they may kill alveolar epithelial cells, while their expression of amphiregulin suggests they may also induce bronchial epithelial cell hyperplasia. CD8+ T cells in SSc-ILD appear to transition from resting to the tissue resident memory phenotype.


Assuntos
Doenças Pulmonares Intersticiais , Escleroderma Sistêmico , Linfócitos T Reguladores , Humanos , Anfirregulina , Linfócitos T CD8-Positivos , Células Matadoras Naturais , Pulmão , Doenças Pulmonares Intersticiais/imunologia , Células T de Memória , Escleroderma Sistêmico/imunologia
14.
Exp Dermatol ; 33(10): e70000, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39422315

RESUMO

The epidermis, the most superficial layer of the human skin, serves a critical barrier function, protecting the body from external pathogens and allergens. Dysregulation of epidermal differentiation contributes to barrier dysfunction and has been implicated in the pathology of various dermatological diseases, including atopic dermatitis (AD). Mucopolysaccharide polysulphate (MPS) is a moisturising agent used to treat xerosis in patients with AD. However, its mechanism of action on keratinocytes, the main constituents of the epidermis, remains unclear. In this study, we investigated the effect of MPS on keratinocytes by subjecting adult human epidermal and three-dimensional cultured keratinocytes to MPS treatment, followed by transcriptome analysis. The analysis revealed that MPS treatment enhances keratinocyte differentiation and suppresses proliferation. We focused on amphiregulin (AREG), a membrane protein that belongs to the epidermal growth factor (EGF) family and possesses a heparin-binding domain, as a significant target among the genes altered by MPS. MPS exerted an inhibitory effect directly on AREG, rather than on EGF receptors or other members of the EGF family. Furthermore, AREG leads to a reduction in epidermal barrier function, whereas MPS contributes to barrier enhancement via AREG inhibition. Collectively, these findings suggest that MPS modulates barrier function through AREG inhibition, offering insights into potential therapeutic strategies for skin barrier restoration.


Assuntos
Anfirregulina , Queratinócitos , Fosfatos , Polissacarídeos , Humanos , Anfirregulina/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Epiderme/metabolismo , Epiderme/efeitos dos fármacos , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inibidores , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Polissacarídeos/farmacologia , Fosfatos/farmacologia
15.
Exp Eye Res ; 247: 110059, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39181228

RESUMO

The purpose of the experimental interventional study was to examine the influence of intraocularly applied amphiregulin, a member of the epidermal growth factor (EGF) family, on axial length in young non-human primates. It included three non-human primates (Macaca mulatta), aged 4-6 years. The left eyes received three intravitreal injections of amphiregulin (400ng/50 µl) in intervals of 4 weeks, while the right eyes received three intravitreal injections of phosphate buffered solution (50 µl) at the same time points. Ocular biometry was performed in weekly intervals. At baseline, the left eyes (study eyes) were shorter than the right (control) eyes (20.69 ± 0.21 mm versus 20.79 ± 0.24 mm; P < 0.001), with an inter-eye axial length (AL) difference (left minus right eye) of -0.10 ± 0.23 mm. Inter-eye AL difference increased (P < 0.001) to 0.15 ± 0.18 mm at study end, at 12 weeks after baseline. Axial elongation during the study was higher (P < 0.001) in the left eyes (20.69 ± 0.21 mm to 21.05 ± 0.29 mm or 0.36 ± 0.30 mm) than in the right eyes (20.79 ± 0.24 mm to 20.90 ± 0.31 mm or 0.11 ± 0.17 mm). In a parallel manner, inter-eye difference in vitreous cavity depth combined with lens thickness (left eye minus right eye) increased from -0.04 ± 0.17 mm at baseline to -0.02 ± 0.21 mm (P = 0.02), 0.04 ± 0.10 mm (P = 0.002), and to 0.42 ± 0.67 mm (P < 0.001) at 5, 6, and 12 weeks after baseline, respectively. The results suggest that intravitreally applied amphiregulin as EGF family member led to an increase in axial length in adolescent non-human primates. It supports the hypothesis of amphiregulin as EGF family member being involved in the process of axial elongation.


Assuntos
Anfirregulina , Comprimento Axial do Olho , Animais , Feminino , Masculino , Anfirregulina/administração & dosagem , Comprimento Axial do Olho/efeitos dos fármacos , Biometria , Injeções Intravítreas , Macaca mulatta , Miopia/metabolismo , Miopia/fisiopatologia
16.
J Oral Pathol Med ; 53(6): 366-375, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38763759

RESUMO

BACKGROUND: Angiopoietin-like 4 is a molecular hallmark that correlates with the growth and metastasis of head and neck squamous cell carcinoma, one of the most prevalent cancers worldwide. However, the molecular mechanisms by which angiopoietin-like 4 promotes head and neck squamous cell carcinoma tumorigenesis are unclear. METHODS: Using well-characterized cell lines of head and neck squamous cell carcinoma development, including human normal oral keratinocytes, dysplastic oral keratinocytes, oral leukoplakia-derived oral keratinocytes, and head and neck squamous cell carcinoma cell lines, HN13, HN6, HN4, HN12, and CAL27, we investigated the signaling pathways upstream and downstream of angiopoietin-like 4-induced head and neck squamous cell carcinoma tumorigenesis. RESULTS: We found that both epidermal growth factor receptor ligands, epithelial growth factor, and amphiregulin led to angiopoietin-like 4 upregulation in normal oral keratinocytes and dysplastic oral keratinocytes and cooperated with the activation of hypoxia-inducible factor-1 in this effect. Interestingly, amphiregulin and angiopoietin-like 4 were increased in dysplastic oral keratinocytes and head and neck squamous cell carcinoma cell lines, and amphiregulin-induced activation of cell proliferation was dependent on angiopoietin-like 4. Although both p38 mitogen-activated protein kinases (p38 MAPK) and protein kinase B (AKT) were activated by angiopoietin-like 4, only pharmacological inhibition of p38 MAPK was sufficient to prevent head and neck squamous cell carcinoma cell proliferation and migration. We further observed that angiopoietin-like 4 promoted the secretion of interleukin 11 (IL-11), interleukin 12 (IL-12), interleukin-1 alpha (IL-1α), vascular endothelial growth factor, platelet-derived growth factor (PDGF), and tumour necrosis factor alpha (TNF-α), cytokines and chemokines previously implicated in head and neck squamous cell carcinoma pathogenesis. CONCLUSION: Our results demonstrate that angiopoietin-like 4 is a downstream effector of amphiregulin and promotes head and neck squamous cell carcinoma development both through direct activation of p38 kinase as well as paracrine mechanisms.


Assuntos
Anfirregulina , Proteína 4 Semelhante a Angiopoietina , Movimento Celular , Proliferação de Células , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas de Cabeça e Pescoço , Regulação para Cima , Proteínas Quinases p38 Ativadas por Mitógeno , Humanos , Anfirregulina/farmacologia , Anfirregulina/metabolismo , Proliferação de Células/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Movimento Celular/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Proteína 4 Semelhante a Angiopoietina/metabolismo , Linhagem Celular Tumoral , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/metabolismo , Transdução de Sinais , Queratinócitos/metabolismo , Queratinócitos/efeitos dos fármacos , Receptores ErbB/metabolismo
17.
Cell Mol Life Sci ; 80(3): 60, 2023 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-36749397

RESUMO

Amphiregulin (AREG) is an epidermal growth factor (EGF)-like growth factor that binds exclusively to the EGF receptor (EGFR). Treatment with luteinizing hormone (LH) and/or human chorionic gonadotropin dramatically induces the expression of AREG in the granulosa cells of the preovulatory follicle. In addition, AREG is the most abundant EGFR ligand in human follicular fluid. Therefore, AREG is considered a predominant propagator that mediates LH surge-regulated ovarian functions in an autocrine and/or paracrine manner. In addition to the well-characterized stimulatory effect of LH on AREG expression, recent studies discovered that several local factors and epigenetic modifications participate in the regulation of ovarian AREG expression. Moreover, aberrant expression of AREG has recently been reported to contribute to the pathogenesis of several ovarian diseases, such as ovarian hyperstimulation syndrome, polycystic ovary syndrome, and epithelial ovarian cancer. Furthermore, increasing evidence has elucidated new applications of AREG in assisted reproductive technology. Collectively, these studies highlight the importance of AREG in female reproductive health and disease. Understanding the normal and pathological roles of AREG and elucidating the molecular and cellular mechanisms of AREG regulation of ovarian functions will inform innovative approaches for fertility regulation and the prevention and treatment of ovarian diseases. Therefore, this review summarizes the functional roles of AREG in ovarian function and disease.


Assuntos
Fator de Crescimento Epidérmico , Doenças Ovarianas , Feminino , Humanos , Anfirregulina/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Hormônio Luteinizante , Receptores ErbB/metabolismo
18.
Clin Exp Nephrol ; 28(5): 421-430, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38402497

RESUMO

BACKGROUND: Amphiregulin (AREG) is a ligand of epidermal growth factor receptor (EGFR), which plays an important role in injury-induced kidney fibrosis. However, the clinical significance of serum soluble AREG in chronic kidney disease (CKD) is unclear. In this study, we elucidated the clinical significance of serum soluble AREG in CKD by analyzing the association of serum soluble AREG levels with renal function and other clinical parameters in patients with CKD. METHODS: In total, 418 Japanese patients with CKD were enrolled, and serum samples were collected for the determination of soluble AREG and creatinine (Cr) levels, and other clinical parameters. Additionally, these parameters were evaluated after 2 and 3 years. Moreover, immunohistochemical assay was performed ate AREG expression in the kidney tissues of patients with CKD. RESULTS: Soluble AREG levels were positively correlated with serum Cr (p < 0.0001). Notably, initial AREG levels were positively correlated with changes in renal function (ΔCr) after 2 (p < 0.0001) and 3 years (P = 0.048). Additionally, soluble AREG levels were significantly higher (p < 0.05) in patients with diabetic nephropathy or primary hypertension. Moreover, AREG was highly expressed in renal tubular cells in patients with advanced CKD, but only weakly expressed in patients with preserved renal function. CONCLUSION: Serum soluble AREG levels were significantly correlated with renal function, and changes in renal function after 2 and 3 years, indicating that serum soluble AREG levels might serve as a biomarker of renal function and renal prognosis in CKD.


Assuntos
Anfirregulina , Creatinina , Insuficiência Renal Crônica , Humanos , Anfirregulina/sangue , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Creatinina/sangue , Biomarcadores/sangue , Taxa de Filtração Glomerular , Rim/fisiopatologia , Rim/metabolismo , Rim/patologia , Adulto , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/diagnóstico , Hipertensão , Relevância Clínica
19.
Oral Dis ; 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39007193

RESUMO

OBJECTIVE: To analyze the biological effect and mechanism of areca nut extract (ANE) on human oral keratinocyte (HOK) cells. MATERIALS AND METHODS: The effect of gradient concentration of ANE on the proliferation activity of HOK cells was analyzed by cell counting kit-8 (CCK-8) assays. The differentially expressed genes between the ANE group and control group HOK cells were analyzed by second-generation transcriptome sequencing. Real-time PCR and western blot were, respectively, used to analyze the expression of AREG gene and protein in HOK cells. After AREG gene overexpression or knockdown, the proliferation, migration, and expression of proteins related to epithelial-mesenchymal transformation (EMT), MAPK signal pathway in HOK cells were, respectively, detected by CCK-8, wound healing, transwell, and western blot assays. RESULTS: ANE (500 µg/mL) promoted the proliferation and migration of HOK cells, ANE (2 mg/mL) promoted the EMT of HOK cells, and ANE (50 mg/mL) inhibited the proliferation of HOK cells. AREG knockdown inhibited ANE-induced proliferation and migration of HOK cells, while AREG overexpression promoted the proliferation and migration of HOK cells. Western blot assay showed that ANE activated MAPK signal pathway by upregulating AREG protein in HOK cells. CONCLUSIONS: ANE promoted HOK cell proliferation, migration, and EMT by mediating AREG-MAPK signaling pathway.

20.
Proc Natl Acad Sci U S A ; 118(19)2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33941693

RESUMO

Along with blood vessels, lymphatic vessels play an important role in the circulation of body fluid and recruitment of immune cells. Postnatal lymphangiogenesis commonly occurs from preexisting lymphatic vessels by sprouting, which is induced by lymphangiogenic factors such as vascular endothelial growth factor C (VEGF-C). However, the key signals and cell types that stimulate pathological lymphangiogenesis, such as human cystic lymphangioma, are less well known. Here, we found that mouse dermal fibroblasts that infiltrate to sponges subcutaneously implanted express VEGF-D and sushi, Von Willebrand factor type A, EGF, and pentraxin domain containing 1 (SVEP1) in response to PDGFRß signal. In vitro, Pdgfrb knockout (ß-KO) fibroblasts had reduced expression of VEGF-D and SVEP1 and overproduced Amphiregulin. Dysregulation of these three factors was involved in the cyst-like and uneven distribution of lymphatic vessels observed in the ß-KO mice. Similarly, in human cystic lymphangioma, which is one of the intractable diseases and mostly occurs in childhood, fibroblasts surrounding cystic lymphatics highly expressed Amphiregulin. Moreover, fibroblast-derived Amphiregulin could induce the expression of Amphiregulin in lymphatic endothelial cells. The dual source of Amphiregulin activated EGFR expressed on the lymphatic endothelial cells. This exacerbation cascade induced proliferation of lymphatic endothelial cells to form cystic lymphangioma. Ultimately, excessive Amphiregulin produced by fibroblasts surrounding lymphatics and by lymphatic endothelial cells per se results in pathogenesis of cystic lymphangioma and will be a fascinating therapeutic target of cystic lymphangioma.


Assuntos
Anfirregulina/metabolismo , Anfirregulina/farmacologia , Linfangiogênese/efeitos dos fármacos , Linfangiogênese/fisiologia , Linfangioma Cístico/metabolismo , Anfirregulina/genética , Animais , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/metabolismo , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Linfangioma Cístico/genética , Linfangioma Cístico/patologia , Vasos Linfáticos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Fator C de Crescimento do Endotélio Vascular/metabolismo , Fator D de Crescimento do Endotélio Vascular
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