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1.
Annu Rev Immunol ; 39: 537-556, 2021 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-33577346

RESUMO

The IL-17 family is an evolutionarily old cytokine family consisting of six members (IL-17A through IL-17F). IL-17 family cytokines signal through heterodimeric receptors that include the shared IL-17RA subunit, which is widely expressed throughout the body on both hematopoietic and nonhematopoietic cells. The founding family member, IL-17A, is usually referred to as IL-17 and has received the most attention for proinflammatory roles in autoimmune diseases like psoriasis. However, IL-17 is associated with a wide array of diseases with perhaps surprisingly variable pathologies. This review focuses on recent advances in the roles of IL-17 during health and in disease pathogenesis. To decipher the functions of IL-17 in diverse disease processes it is useful to first consider the physiological functions that IL-17 contributes to health. We then discuss how these beneficial functions can be diverted toward pathogenic amplification of deleterious pathways driving chronic disease.


Assuntos
Doenças Autoimunes , Interleucina-17 , Animais , Doenças Autoimunes/etiologia , Citocinas , Humanos , Intenção , Receptores de Interleucina-17
2.
Annu Rev Immunol ; 36: 639-665, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29400999

RESUMO

Granulomas are organized aggregates of macrophages, often with characteristic morphological changes, and other immune cells. These evolutionarily ancient structures form in response to persistent particulate stimuli-infectious or noninfectious-that individual macrophages cannot eradicate. Granulomas evolved as protective responses to destroy or sequester particles but are frequently pathological in the context of foreign bodies, infections, and inflammatory diseases. We summarize recent findings that suggest that the granulomatous response unfolds in a stepwise program characterized by a series of macrophage activations and transformations that in turn recruit additional cells and produce structural changes. We explore why different granulomas vary and the reasons that granulomas are protective and pathogenic. Understanding the mechanisms and role of granuloma formation may uncover new therapies for the multitude of granulomatous diseases that constitute serious medical problems while enhancing the protective function of granulomas in infections.


Assuntos
Granuloma/diagnóstico , Granuloma/etiologia , Animais , Diagnóstico Diferencial , Fibrose , Interações Hospedeiro-Patógeno/imunologia , Humanos , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Necrose , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
3.
Cell ; 187(4): 981-998.e25, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38325365

RESUMO

The female reproductive tract (FRT) undergoes extensive remodeling during reproductive cycling. This recurrent remodeling and how it shapes organ-specific aging remains poorly explored. Using single-cell and spatial transcriptomics, we systematically characterized morphological and gene expression changes occurring in ovary, oviduct, uterus, cervix, and vagina at each phase of the mouse estrous cycle, during decidualization, and into aging. These analyses reveal that fibroblasts play central-and highly organ-specific-roles in FRT remodeling by orchestrating extracellular matrix (ECM) reorganization and inflammation. Our results suggest a model wherein recurrent FRT remodeling over reproductive lifespan drives the gradual, age-related development of fibrosis and chronic inflammation. This hypothesis was directly tested using chemical ablation of cycling, which reduced fibrotic accumulation during aging. Our atlas provides extensive detail into how estrus, pregnancy, and aging shape the organs of the female reproductive tract and reveals the unexpected cost of the recurrent remodeling required for reproduction.


Assuntos
Envelhecimento , Genitália Feminina , Animais , Feminino , Camundongos , Gravidez , Genitália Feminina/citologia , Genitália Feminina/metabolismo , Inflamação/metabolismo , Útero/citologia , Vagina/citologia , Análise de Célula Única
4.
Cell ; 187(6): 1527-1546.e25, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38412860

RESUMO

G protein-coupled receptors (GPCRs) are the largest family of druggable proteins encoded in the human genome, but progress in understanding and targeting them is hindered by the lack of tools to reliably measure their nuanced behavior in physiologically relevant contexts. Here, we developed a collection of compact ONE vector G-protein Optical (ONE-GO) biosensor constructs as a scalable platform that can be conveniently deployed to measure G-protein activation by virtually any GPCR with high fidelity even when expressed endogenously in primary cells. By characterizing dozens of GPCRs across many cell types like primary cardiovascular cells or neurons, we revealed insights into the molecular basis for G-protein coupling selectivity of GPCRs, pharmacogenomic profiles of anti-psychotics on naturally occurring GPCR variants, and G-protein subtype signaling bias by endogenous GPCRs depending on cell type or upon inducing disease-like states. In summary, this open-source platform makes the direct interrogation of context-dependent GPCR activity broadly accessible.


Assuntos
Técnicas Biossensoriais , Transdução de Sinais , Humanos , Receptores Acoplados a Proteínas G/metabolismo , Proteínas de Ligação ao GTP/metabolismo
5.
Cell ; 186(18): 3793-3809.e26, 2023 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-37562401

RESUMO

Hepatocytes, the major metabolic hub of the body, execute functions that are human-specific, altered in human disease, and currently thought to be regulated through endocrine and cell-autonomous mechanisms. Here, we show that key metabolic functions of human hepatocytes are controlled by non-parenchymal cells (NPCs) in their microenvironment. We developed mice bearing human hepatic tissue composed of human hepatocytes and NPCs, including human immune, endothelial, and stellate cells. Humanized livers reproduce human liver architecture, perform vital human-specific metabolic/homeostatic processes, and model human pathologies, including fibrosis and non-alcoholic fatty liver disease (NAFLD). Leveraging species mismatch and lipidomics, we demonstrate that human NPCs control metabolic functions of human hepatocytes in a paracrine manner. Mechanistically, we uncover a species-specific interaction whereby WNT2 secreted by sinusoidal endothelial cells controls cholesterol uptake and bile acid conjugation in hepatocytes through receptor FZD5. These results reveal the essential microenvironmental regulation of hepatic metabolism and its human-specific aspects.


Assuntos
Células Endoteliais , Fígado , Animais , Humanos , Camundongos , Células Endoteliais/metabolismo , Hepatócitos/metabolismo , Células de Kupffer/metabolismo , Fígado/citologia , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fibrose/metabolismo
6.
Cell ; 185(8): 1373-1388.e20, 2022 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-35381199

RESUMO

Systemic sclerosis (scleroderma, SSc) is an incurable autoimmune disease with high morbidity and mortality rates. Here, we conducted a population-scale single-cell genomic analysis of skin and blood samples of 56 healthy controls and 97 SSc patients at different stages of the disease. We found immune compartment dysfunction only in a specific subtype of diffuse SSc patients but global dysregulation of the stromal compartment, particularly in a previously undefined subset of LGR5+-scleroderma-associated fibroblasts (ScAFs). ScAFs are perturbed morphologically and molecularly in SSc patients. Single-cell multiome profiling of stromal cells revealed ScAF-specific markers, pathways, regulatory elements, and transcription factors underlining disease development. Systematic analysis of these molecular features with clinical metadata associates specific ScAF targets with disease pathogenesis and SSc clinical traits. Our high-resolution atlas of the sclerodermatous skin spectrum will enable a paradigm shift in the understanding of SSc disease and facilitate the development of biomarkers and therapeutic strategies.


Assuntos
Escleroderma Sistêmico , Células Cultivadas , Fibroblastos/metabolismo , Fibrose , Humanos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/genética , Pele/metabolismo
7.
Cell ; 185(1): 158-168.e11, 2022 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-34995514

RESUMO

Small molecule chaperones have been exploited as therapeutics for the hundreds of diseases caused by protein misfolding. The most successful examples are the CFTR correctors, which transformed cystic fibrosis therapy. These molecules revert folding defects of the ΔF508 mutant and are widely used to treat patients. To investigate the molecular mechanism of their action, we determined cryo-electron microscopy structures of CFTR in complex with the FDA-approved correctors lumacaftor or tezacaftor. Both drugs insert into a hydrophobic pocket in the first transmembrane domain (TMD1), linking together four helices that are thermodynamically unstable. Mutating residues at the binding site rendered ΔF508-CFTR insensitive to lumacaftor and tezacaftor, underscoring the functional significance of the structural discovery. These results support a mechanism in which the correctors stabilize TMD1 at an early stage of biogenesis, prevent its premature degradation, and thereby allosterically rescuing many disease-causing mutations.


Assuntos
Aminopiridinas/metabolismo , Benzodioxóis/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Indóis/metabolismo , Dobramento de Proteína , Aminopiridinas/química , Aminopiridinas/uso terapêutico , Animais , Benzodioxóis/química , Benzodioxóis/uso terapêutico , Sítios de Ligação , Células CHO , Membrana Celular/química , Membrana Celular/metabolismo , Cricetulus , Microscopia Crioeletrônica , Fibrose Cística/tratamento farmacológico , Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/química , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Células HEK293 , Humanos , Interações Hidrofóbicas e Hidrofílicas , Indóis/química , Indóis/uso terapêutico , Chaperonas Moleculares/química , Chaperonas Moleculares/metabolismo , Chaperonas Moleculares/uso terapêutico , Mutação , Domínios Proteicos/genética , Células Sf9 , Transfecção
8.
Cell ; 185(11): 1860-1874.e12, 2022 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-35568033

RESUMO

Two mycobacteriophages were administered intravenously to a male with treatment-refractory Mycobacterium abscessus pulmonary infection and severe cystic fibrosis lung disease. The phages were engineered to enhance their capacity to lyse M. abscessus and were selected specifically as the most effective against the subject's bacterial isolate. In the setting of compassionate use, the evidence of phage-induced lysis was observed using molecular and metabolic assays combined with clinical assessments. M. abscessus isolates pre and post-phage treatment demonstrated genetic stability, with a general decline in diversity and no increased resistance to phage or antibiotics. The anti-phage neutralizing antibody titers to one phage increased with time but did not prevent clinical improvement throughout the course of treatment. The subject received lung transplantation on day 379, and systematic culturing of the explanted lung did not detect M. abscessus. This study describes the course and associated markers of a successful phage treatment of M. abscessus in advanced lung disease.


Assuntos
Bacteriófagos , Fibrose Cística , Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bacteriófagos/genética , Fibrose Cística/tratamento farmacológico , Humanos , Pulmão , Masculino , Infecções por Mycobacterium não Tuberculosas/terapia , Mycobacterium abscessus/fisiologia
9.
Cell ; 184(26): 6243-6261.e27, 2021 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-34914922

RESUMO

COVID-19-induced "acute respiratory distress syndrome" (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyze pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single-cell genomics, immunohistology, and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS.


Assuntos
COVID-19/patologia , COVID-19/virologia , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/virologia , Macrófagos/patologia , Macrófagos/virologia , SARS-CoV-2/fisiologia , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , COVID-19/diagnóstico por imagem , Comunicação Celular , Estudos de Coortes , Fibroblastos/patologia , Regulação da Expressão Gênica , Humanos , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Fibrose Pulmonar Idiopática/genética , Células-Tronco Mesenquimais/patologia , Fenótipo , Proteoma/metabolismo , Receptores de Superfície Celular/metabolismo , Síndrome do Desconforto Respiratório/diagnóstico por imagem , Síndrome do Desconforto Respiratório/patologia , Síndrome do Desconforto Respiratório/virologia , Tomografia Computadorizada por Raios X , Transcrição Gênica
10.
Cell ; 184(3): 775-791.e14, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33503446

RESUMO

The molecular pathology of multi-organ injuries in COVID-19 patients remains unclear, preventing effective therapeutics development. Here, we report a proteomic analysis of 144 autopsy samples from seven organs in 19 COVID-19 patients. We quantified 11,394 proteins in these samples, in which 5,336 were perturbed in the COVID-19 patients compared to controls. Our data showed that cathepsin L1, rather than ACE2, was significantly upregulated in the lung from the COVID-19 patients. Systemic hyperinflammation and dysregulation of glucose and fatty acid metabolism were detected in multiple organs. We also observed dysregulation of key factors involved in hypoxia, angiogenesis, blood coagulation, and fibrosis in multiple organs from the COVID-19 patients. Evidence for testicular injuries includes reduced Leydig cells, suppressed cholesterol biosynthesis, and sperm mobility. In summary, this study depicts a multi-organ proteomic landscape of COVID-19 autopsies that furthers our understanding of the biological basis of COVID-19 pathology.


Assuntos
COVID-19/metabolismo , Regulação da Expressão Gênica , Proteoma/biossíntese , Proteômica , SARS-CoV-2/metabolismo , Autopsia , COVID-19/patologia , COVID-19/terapia , Feminino , Humanos , Masculino , Especificidade de Órgãos
11.
Cell ; 184(10): 2537-2564, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33989548

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide. Its more advanced subtype, nonalcoholic steatohepatitis (NASH), connotes progressive liver injury that can lead to cirrhosis and hepatocellular carcinoma. Here we provide an in-depth discussion of the underlying pathogenetic mechanisms that lead to progressive liver injury, including the metabolic origins of NAFLD, the effect of NAFLD on hepatic glucose and lipid metabolism, bile acid toxicity, macrophage dysfunction, and hepatic stellate cell activation, and consider the role of genetic, epigenetic, and environmental factors that promote fibrosis progression and risk of hepatocellular carcinoma in NASH.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Carcinoma Hepatocelular/patologia , Humanos , Fígado/patologia , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/patologia
12.
Cell ; 184(8): 1990-2019, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33811810

RESUMO

The population is aging at a rate never seen before in human history. As the number of elderly adults grows, it is imperative we expand our understanding of the underpinnings of aging biology. Human lungs are composed of a unique panoply of cell types that face ongoing chemical, mechanical, biological, immunological, and xenobiotic stress over a lifetime. Yet, we do not fully appreciate the mechanistic drivers of lung aging and why age increases the risk of parenchymal lung disease, fatal respiratory infection, and primary lung cancer. Here, we review the molecular and cellular aspects of lung aging, local stress response pathways, and how the aging process predisposes to the pathogenesis of pulmonary disease. We place these insights into context of the COVID-19 pandemic and discuss how innate and adaptive immunity within the lung is altered with age.


Assuntos
Envelhecimento , Senescência Celular , Pneumopatias , Pulmão , Imunidade Adaptativa , Idoso , Envelhecimento/imunologia , Envelhecimento/patologia , COVID-19/imunologia , COVID-19/patologia , Humanos , Pulmão/imunologia , Pulmão/patologia , Pneumopatias/imunologia , Pneumopatias/patologia , Estresse Oxidativo
13.
Cell ; 183(3): 666-683.e17, 2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-32991841

RESUMO

A mysterious feature of Crohn's disease (CD) is the extra-intestinal manifestation of "creeping fat" (CrF), defined as expansion of mesenteric adipose tissue around the inflamed and fibrotic intestine. In the current study, we explore whether microbial translocation in CD serves as a central cue for CrF development. We discovered a subset of mucosal-associated gut bacteria that consistently translocated and remained viable in CrF in CD ileal surgical resections, and identified Clostridium innocuum as a signature of this consortium with strain variation between mucosal and adipose isolates, suggesting preference for lipid-rich environments. Single-cell RNA sequencing characterized CrF as both pro-fibrotic and pro-adipogenic with a rich milieu of activated immune cells responding to microbial stimuli, which we confirm in gnotobiotic mice colonized with C. innocuum. Ex vivo validation of expression patterns suggests C. innocuum stimulates tissue remodeling via M2 macrophages, leading to an adipose tissue barrier that serves to prevent systemic dissemination of bacteria.


Assuntos
Tecido Adiposo/microbiologia , Translocação Bacteriana , Microbioma Gastrointestinal , Mesentério/microbiologia , Tecido Adiposo/patologia , Animais , Biodiversidade , Biomarcadores/metabolismo , Polaridade Celular , Células Cultivadas , Colite Ulcerativa/patologia , Doença de Crohn/microbiologia , Doença de Crohn/patologia , Microbioma Gastrointestinal/genética , Regulação da Expressão Gênica , Vida Livre de Germes , Humanos , Íleo/microbiologia , Íleo/patologia , Lipopolissacarídeos/metabolismo , Macrófagos/metabolismo , Metagenoma , Metagenômica , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , RNA Ribossômico 16S/genética , Células-Tronco/metabolismo
14.
Cell ; 181(4): 848-864.e18, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32298651

RESUMO

Chronic obstructive pulmonary disease (COPD) is a progressive condition of chronic bronchitis, small airway obstruction, and emphysema that represents a leading cause of death worldwide. While inflammation, fibrosis, mucus hypersecretion, and metaplastic epithelial lesions are hallmarks of this disease, their origins and dependent relationships remain unclear. Here we apply single-cell cloning technologies to lung tissue of patients with and without COPD. Unlike control lungs, which were dominated by normal distal airway progenitor cells, COPD lungs were inundated by three variant progenitors epigenetically committed to distinct metaplastic lesions. When transplanted to immunodeficient mice, these variant clones induced pathology akin to the mucous and squamous metaplasia, neutrophilic inflammation, and fibrosis seen in COPD. Remarkably, similar variants pre-exist as minor constituents of control and fetal lung and conceivably act in normal processes of immune surveillance. However, these same variants likely catalyze the pathologic and progressive features of COPD when expanded to high numbers.


Assuntos
Pulmão/patologia , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Adulto , Idoso , Animais , Feminino , Fibrose/fisiopatologia , Humanos , Inflamação/patologia , Pulmão/metabolismo , Masculino , Metaplasia/fisiopatologia , Camundongos , Pessoa de Meia-Idade , Neutrófilos/imunologia , Pneumonia/patologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Análise de Célula Única/métodos , Células-Tronco/metabolismo
15.
Cell ; 182(3): 545-562.e23, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32621799

RESUMO

Scar tissue size following myocardial infarction is an independent predictor of cardiovascular outcomes, yet little is known about factors regulating scar size. We demonstrate that collagen V, a minor constituent of heart scars, regulates the size of heart scars after ischemic injury. Depletion of collagen V led to a paradoxical increase in post-infarction scar size with worsening of heart function. A systems genetics approach across 100 in-bred strains of mice demonstrated that collagen V is a critical driver of postinjury heart function. We show that collagen V deficiency alters the mechanical properties of scar tissue, and altered reciprocal feedback between matrix and cells induces expression of mechanosensitive integrins that drive fibroblast activation and increase scar size. Cilengitide, an inhibitor of specific integrins, rescues the phenotype of increased post-injury scarring in collagen-V-deficient mice. These observations demonstrate that collagen V regulates scar size in an integrin-dependent manner.


Assuntos
Cicatriz/metabolismo , Colágeno Tipo V/deficiência , Colágeno Tipo V/metabolismo , Traumatismos Cardíacos/metabolismo , Contração Miocárdica/genética , Miofibroblastos/metabolismo , Animais , Cicatriz/genética , Cicatriz/fisiopatologia , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Cadeia alfa 1 do Colágeno Tipo I , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Colágeno Tipo V/genética , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Feminino , Fibrose/genética , Fibrose/metabolismo , Regulação da Expressão Gênica/genética , Integrinas/antagonistas & inibidores , Integrinas/genética , Integrinas/metabolismo , Isoproterenol/farmacologia , Masculino , Mecanotransdução Celular/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia de Força Atômica/instrumentação , Microscopia Eletrônica de Transmissão , Contração Miocárdica/efeitos dos fármacos , Miofibroblastos/citologia , Miofibroblastos/patologia , Miofibroblastos/ultraestrutura , Análise de Componente Principal , Proteômica , RNA-Seq , Análise de Célula Única
16.
Cell ; 178(6): 1478-1492.e20, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31474362

RESUMO

Liver fibrosis is a very common condition seen in millions of patients with various liver diseases, and yet no effective treatments are available owing to poorly characterized molecular pathogenesis. Here, we show that leukocyte cell-derived chemotaxin 2 (LECT2) is a functional ligand of Tie1, a poorly characterized endothelial cell (EC)-specific orphan receptor. Upon binding to Tie1, LECT2 interrupts Tie1/Tie2 heterodimerization, facilitates Tie2/Tie2 homodimerization, activates PPAR signaling, and inhibits the migration and tube formations of EC. In vivo studies showed that LECT2 overexpression inhibits portal angiogenesis, promotes sinusoid capillarization, and worsens fibrosis, whereas these changes were reversed in Lect2-KO mice. Adeno-associated viral vector serotype 9 (AAV9)-LECT2 small hairpin RNA (shRNA) treatment significantly attenuates fibrosis. Upregulation of LECT2 is associated with advanced human liver fibrosis staging. We concluded that targeting LECT2/Tie1 signaling may represent a potential therapeutic target for liver fibrosis, and serum LECT2 level may be a potential biomarker for the screening and diagnosis of liver fibrosis.


Assuntos
Células Endoteliais/metabolismo , Hepatócitos/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Cirrose Hepática/metabolismo , Fígado/metabolismo , Receptores de TIE/metabolismo , Animais , Biomarcadores/metabolismo , Capilares/metabolismo , Células Endoteliais/citologia , Células Endoteliais/patologia , Células HEK293 , Hepatócitos/citologia , Hepatócitos/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Fígado/irrigação sanguínea , Fígado/patologia , Cirrose Hepática/diagnóstico , Camundongos Endogâmicos C57BL
17.
Cell ; 176(6): 1340-1355.e15, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30799037

RESUMO

Th17 cells provide protection at barrier tissues but may also contribute to immune pathology. The relevance and induction mechanisms of pathologic Th17 responses in humans are poorly understood. Here, we identify the mucocutaneous pathobiont Candida albicans as the major direct inducer of human anti-fungal Th17 cells. Th17 cells directed against other fungi are induced by cross-reactivity to C. albicans. Intestinal inflammation expands total C. albicans and cross-reactive Th17 cells. Strikingly, Th17 cells cross-reactive to the airborne fungus Aspergillus fumigatus are selectively activated and expanded in patients with airway inflammation, especially during acute allergic bronchopulmonary aspergillosis. This indicates a direct link between protective intestinal Th17 responses against C. albicans and lung inflammation caused by airborne fungi. We identify heterologous immunity to a single, ubiquitous member of the microbiota as a central mechanism for systemic induction of human anti-fungal Th17 responses and as a potential risk factor for pulmonary inflammatory diseases.


Assuntos
Candida albicans/imunologia , Células Th17/imunologia , Células Th17/metabolismo , Aspergillus fumigatus/imunologia , Aspergillus fumigatus/patogenicidade , Candida albicans/patogenicidade , Reações Cruzadas/imunologia , Fibrose Cística/imunologia , Fibrose Cística/microbiologia , Humanos , Imunidade , Imunidade Heteróloga/imunologia , Células Th17/fisiologia
18.
Immunity ; 57(2): 303-318.e6, 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38309273

RESUMO

Production of amphiregulin (Areg) by regulatory T (Treg) cells promotes repair after acute tissue injury. Here, we examined the function of Treg cells in non-alcoholic steatohepatitis (NASH), a setting of chronic liver injury. Areg-producing Treg cells were enriched in the livers of mice and humans with NASH. Deletion of Areg in Treg cells, but not in myeloid cells, reduced NASH-induced liver fibrosis. Chronic liver damage induced transcriptional changes associated with Treg cell activation. Mechanistically, Treg cell-derived Areg activated pro-fibrotic transcriptional programs in hepatic stellate cells via epidermal growth factor receptor (EGFR) signaling. Deletion of Areg in Treg cells protected mice from NASH-dependent glucose intolerance, which also was dependent on EGFR signaling on hepatic stellate cells. Areg from Treg cells promoted hepatocyte gluconeogenesis through hepatocyte detection of hepatic stellate cell-derived interleukin-6. Our findings reveal a maladaptive role for Treg cell-mediated tissue repair functions in chronic liver disease and link liver damage to NASH-dependent glucose intolerance.


Assuntos
Intolerância à Glucose , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Animais , Humanos , Camundongos , Anfirregulina/genética , Anfirregulina/metabolismo , Receptores ErbB/metabolismo , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Fígado/metabolismo , Cirrose Hepática/metabolismo , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/patologia , Linfócitos T Reguladores/metabolismo
19.
Immunity ; 57(6): 1306-1323.e8, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38815582

RESUMO

Group 3 innate lymphoid cells (ILC3s) regulate inflammation and tissue repair at mucosal sites, but whether these functions pertain to other tissues-like the kidneys-remains unclear. Here, we observed that renal fibrosis in humans was associated with increased ILC3s in the kidneys and blood. In mice, we showed that CXCR6+ ILC3s rapidly migrated from the intestinal mucosa and accumulated in the kidney via CXCL16 released from the injured tubules. Within the fibrotic kidney, ILC3s increased the expression of programmed cell death-1 (PD-1) and subsequent IL-17A production to directly activate myofibroblasts and fibrotic niche formation. ILC3 expression of PD-1 inhibited IL-23R endocytosis and consequently amplified the JAK2/STAT3/RORγt/IL-17A pathway that was essential for the pro-fibrogenic effect of ILC3s. Thus, we reveal a hitherto unrecognized migration pathway of ILC3s from the intestine to the kidney and the PD-1-dependent function of ILC3s in promoting renal fibrosis.


Assuntos
Movimento Celular , Fibrose , Rim , Linfócitos , Receptor de Morte Celular Programada 1 , Receptores CXCR6 , Receptores de Interleucina , Transdução de Sinais , Animais , Fibrose/imunologia , Camundongos , Receptores CXCR6/metabolismo , Receptores CXCR6/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais/imunologia , Movimento Celular/imunologia , Humanos , Rim/patologia , Rim/imunologia , Rim/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Receptores de Interleucina/metabolismo , Receptores de Interleucina/imunologia , Camundongos Endogâmicos C57BL , Nefropatias/imunologia , Nefropatias/metabolismo , Nefropatias/patologia , Imunidade Inata/imunologia , Camundongos Knockout , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Intestinos/imunologia , Intestinos/patologia
20.
Cell ; 175(2): 530-543.e24, 2018 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-30220458

RESUMO

The occurrence of a spontaneous nephropathy with intranuclear inclusions in laboratory mice has puzzled pathologists for over 4 decades, because its etiology remains elusive. The condition is more severe in immunodeficient animals, suggesting an infectious cause. Using metagenomics, we identify the causative agent as an atypical virus, termed "mouse kidney parvovirus" (MKPV), belonging to a divergent genus of Parvoviridae. MKPV was identified in animal facilities in Australia and North America, is transmitted via a fecal-oral or urinary-oral route, and is controlled by the adaptive immune system. Detailed analysis of the clinical course and histopathological features demonstrated a stepwise progression of pathology ranging from sporadic tubular inclusions to tubular degeneration and interstitial fibrosis and culminating in renal failure. In summary, we identify a widely distributed pathogen in laboratory mice and establish MKPV-induced nephropathy as a new tool for elucidating mechanisms of tubulointerstitial fibrosis that shares molecular features with chronic kidney disease in humans.


Assuntos
Nefrite Intersticial/virologia , Parvovirus/isolamento & purificação , Parvovirus/patogenicidade , Animais , Austrália , Progressão da Doença , Feminino , Fibrose/patologia , Fibrose/virologia , Humanos , Rim/metabolismo , Rim/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nefrite Intersticial/fisiopatologia , América do Norte , Infecções por Parvoviridae/metabolismo
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