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1.
Nat Immunol ; 24(9): 1423-1433, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37474654

RESUMO

Fibrosis, defined by the excess deposition of structural and matricellular proteins in the extracellular space, underlies tissue dysfunction in multiple chronic diseases. Approved antifibrotics have proven modest in efficacy, and the immune compartment remains, for the most part, an untapped therapeutic opportunity. Recent single-cell analyses have interrogated human fibrotic tissues, including immune cells. These studies have revealed a conserved profile of scar-associated macrophages, which localize to the fibrotic niche and interact with mesenchymal cells that produce pathological extracellular matrix. Here we review recent advances in the understanding of the fibrotic microenvironment in human diseases, with a focus on immune cell profiles and functional immune-stromal interactions. We also discuss the key role of the immune system in mediating fibrosis regression and highlight avenues for future study to elucidate potential approaches to targeting inflammatory cells in fibrotic disorders.


Assuntos
Matriz Extracelular , Humanos , Fibrose , Matriz Extracelular/metabolismo
2.
J Hepatol ; 79(2): 296-313, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37224925

RESUMO

BACKGROUND & AIMS: The progression of non-alcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. The gut-liver axis contributes to NASH, but the mechanisms involved and the consequences for NASH-induced fibrosis and liver cancer remain unknown. We investigated the role of gastrointestinal B cells in the development of NASH, fibrosis and NASH-induced HCC. METHODS: C57BL/6J wild-type (WT), B cell-deficient and different immunoglobulin-deficient or transgenic mice were fed distinct NASH-inducing diets or standard chow for 6 or 12 months, whereafter NASH, fibrosis, and NASH-induced HCC were assessed and analysed. Specific pathogen-free/germ-free WT and µMT mice (containing B cells only in the gastrointestinal tract) were fed a choline-deficient high-fat diet, and treated with an anti-CD20 antibody, whereafter NASH and fibrosis were assessed. Tissue biopsy samples from patients with simple steatosis, NASH and cirrhosis were analysed to correlate the secretion of immunoglobulins to clinicopathological features. Flow cytometry, immunohistochemistry and single-cell RNA-sequencing analysis were performed in liver and gastrointestinal tissue to characterise immune cells in mice and humans. RESULTS: Activated intestinal B cells were increased in mouse and human NASH samples and licensed metabolic T-cell activation to induce NASH independently of antigen specificity and gut microbiota. Genetic or therapeutic depletion of systemic or gastrointestinal B cells prevented or reverted NASH and liver fibrosis. IgA secretion was necessary for fibrosis induction by activating CD11b+CCR2+F4/80+CD11c-FCGR1+ hepatic myeloid cells through an IgA-FcR signalling axis. Similarly, patients with NASH had increased numbers of activated intestinal B cells; additionally, we observed a positive correlation between IgA levels and activated FcRg+ hepatic myeloid cells, as well the extent of liver fibrosis. CONCLUSIONS: Intestinal B cells and the IgA-FcR signalling axis represent potential therapeutic targets for the treatment of NASH. IMPACT AND IMPLICATIONS: There is currently no effective treatment for non-alcoholic steatohepatitis (NASH), which is associated with a substantial healthcare burden and is a growing risk factor for hepatocellular carcinoma (HCC). We have previously shown that NASH is an auto-aggressive condition aggravated, amongst others, by T cells. Therefore, we hypothesized that B cells might have a role in disease induction and progression. Our present work highlights that B cells have a dual role in NASH pathogenesis, being implicated in the activation of auto-aggressive T cells and the development of fibrosis via activation of monocyte-derived macrophages by secreted immunoglobulins (e.g., IgA). Furthermore, we show that the absence of B cells prevented HCC development. B cell-intrinsic signalling pathways, secreted immunoglobulins, and interactions of B cells with other immune cells are potential targets for combinatorial NASH therapies against inflammation and fibrosis.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Microbiota , Hepatopatia Gordurosa não Alcoólica , Humanos , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/complicações , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/genética , Camundongos Endogâmicos C57BL , Fígado/patologia , Fibrose , Cirrose Hepática/complicações , Camundongos Transgênicos , Imunoglobulina A/metabolismo , Imunoglobulina A/farmacologia , Modelos Animais de Doenças , Dieta Hiperlipídica/efeitos adversos
3.
Hepatology ; 75(5): 1081-1094, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-34651315

RESUMO

BACKGROUND AND AIMS: Genome-wide association studies (GWAS) have identified several risk loci for gallstone disease. As with most polygenic traits, it is likely that many genetic determinants are undiscovered. The aim of this study was to identify genetic variants that represent new targets for gallstone research and treatment. APPROACH AND RESULTS: We performed a GWAS of 28,627 gallstone cases and 348,373 controls in the UK Biobank, replicated findings in a Scottish cohort (1089 cases, 5228 controls), and conducted a GWA meta-analysis (43,639 cases, 506,798 controls) with the FinnGen cohort. We assessed pathway enrichment using gene-based then gene-set analysis and tissue expression of identified genes in Genotype-Tissue Expression project data. We constructed a polygenic risk score (PRS) and evaluated phenotypic traits associated with the score. Seventy-five risk loci were identified (p < 5 × 10-8 ), of which 46 were new. Pathway enrichment revealed associations with lipid homeostasis, glucuronidation, phospholipid metabolism, and gastrointestinal motility. Anoctamin 1 (ANO1) and transmembrane Protein 147 (TMEM147), both in novel, replicated loci, are expressed in the gallbladder and gastrointestinal tract. Both regulate gastrointestinal motility. The gallstone risk allele rs7599-A leads to suppression of hepatic TMEM147 expression, suggesting that the protein protects against gallstone formation. The highest decile of the PRS demonstrated a 6-fold increased odds of gallstones compared with the lowest decile. The PRS was strongly associated with increased body mass index, serum liver enzymes, and C-reactive protein concentrations, and decreased lipoprotein cholesterol concentrations. CONCLUSIONS: This GWAS demonstrates the polygenic nature of gallstone risk and identifies 46 novel susceptibility loci. We implicate genes influencing gastrointestinal motility in the pathogenesis of gallstones.


Assuntos
Cálculos Biliares , Estudo de Associação Genômica Ampla , Cálculos Biliares/genética , Cálculos Biliares/metabolismo , Motilidade Gastrointestinal , Predisposição Genética para Doença/genética , Humanos , Polimorfismo de Nucleotídeo Único , População Branca
4.
Blood ; 136(25): 2893-2904, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-32614947

RESUMO

Hematopoietic stem and progenitor cells (HSPCs) develop in distinct waves at various anatomical sites during embryonic development. The in vitro differentiation of human pluripotent stem cells (hPSCs) recapitulates some of these processes; however, it has proven difficult to generate functional hematopoietic stem cells (HSCs). To define the dynamics and heterogeneity of HSPCs that can be generated in vitro from hPSCs, we explored single-cell RNA sequencing (scRNAseq) in combination with single-cell protein expression analysis. Bioinformatics analyses and functional validation defined the transcriptomes of naïve progenitors and erythroid-, megakaryocyte-, and leukocyte-committed progenitors, and we identified CD44, CD326, ICAM2/CD9, and CD18, respectively, as markers of these progenitors. Using an artificial neural network that we trained on scRNAseq derived from human fetal liver, we identified a wide range of hPSC-derived HSPCs phenotypes, including a small group classified as HSCs. This transient HSC-like population decreased as differentiation proceeded, and was completely missing in the data set that had been generated using cells selected on the basis of CD43 expression. By comparing the single-cell transcriptome of in vitro-generated HSC-like cells with those generated within the fetal liver, we identified transcription factors and molecular pathways that can be explored in the future to improve the in vitro production of HSCs.


Assuntos
Antígenos de Diferenciação , Células-Tronco Hematopoéticas , Aprendizado de Máquina , Células-Tronco Pluripotentes , RNA-Seq , Análise de Célula Única , Antígenos de Diferenciação/biossíntese , Antígenos de Diferenciação/genética , Feto/citologia , Feto/metabolismo , Regulação da Expressão Gênica , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Fígado/citologia , Fígado/metabolismo , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo
5.
J Am Soc Nephrol ; 31(12): 2833-2854, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32978267

RESUMO

BACKGROUND: Little is known about the roles of myeloid cell subsets in kidney injury and in the limited ability of the organ to repair itself. Characterizing these cells based only on surface markers using flow cytometry might not provide a full phenotypic picture. Defining these cells at the single-cell, transcriptomic level could reveal myeloid heterogeneity in the progression and regression of kidney disease. METHODS: Integrated droplet- and plate-based single-cell RNA sequencing were used in the murine, reversible, unilateral ureteric obstruction model to dissect the transcriptomic landscape at the single-cell level during renal injury and the resolution of fibrosis. Paired blood exchange tracked the fate of monocytes recruited to the injured kidney. RESULTS: A single-cell atlas of the kidney generated using transcriptomics revealed marked changes in the proportion and gene expression of renal cell types during injury and repair. Conventional flow cytometry markers would not have identified the 12 myeloid cell subsets. Monocytes recruited to the kidney early after injury rapidly adopt a proinflammatory, profibrotic phenotype that expresses Arg1, before transitioning to become Ccr2+ macrophages that accumulate in late injury. Conversely, a novel Mmp12+ macrophage subset acts during repair. CONCLUSIONS: Complementary technologies identified novel myeloid subtypes, based on transcriptomics in single cells, that represent therapeutic targets to inhibit progression or promote regression of kidney disease.


Assuntos
Nefropatias/etiologia , Nefropatias/patologia , Células Mieloides/fisiologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Nefropatias/metabolismo , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência de RNA , Análise de Célula Única , Obstrução Ureteral/etiologia
8.
Hepatology ; 67(6): 2167-2181, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29251794

RESUMO

A hallmark of chronic liver injury is fibrosis, with accumulation of extracellular matrix orchestrated by activated hepatic stellate cells (HSCs). Glucocorticoids limit HSC activation in vitro, and tissue glucocorticoid levels are amplified by 11beta-hydroxysteroid dehydrogenase-1 (11ßHSD1). Although 11ßHSD1 inhibitors have been developed for type 2 diabetes mellitus and improve diet-induced fatty liver in various mouse models, effects on the progression and/or resolution of liver injury and consequent fibrosis have not been characterized. We have used the reversible carbon tetrachloride-induced model of hepatocyte injury and liver fibrosis to show that in two models of genetic 11ßHSD1 deficiency (global, Hsd11b1-/- , and hepatic myofibroblast-specific, Hsd11b1fl/fl /Pdgfrb-cre) 11ßHSD1 pharmacological inhibition in vivo exacerbates hepatic myofibroblast activation and liver fibrosis. In contrast, liver injury and fibrosis in hepatocyte-specific Hsd11b1fl/fl /albumin-cre mice did not differ from that of controls, ruling out 11ßHSD1 deficiency in hepatocytes as the cause of the increased fibrosis. In primary HSC culture, glucocorticoids inhibited expression of the key profibrotic genes Acta2 and Col1α1, an effect attenuated by the 11ßHSD1 inhibitor [4-(2-chlorophenyl-4-fluoro-1-piperidinyl][5-(1H-pyrazol-4-yl)-3-thienyl]-methanone. HSCs from Hsd11b1-/- and Hsd11b1fl/fl /Pdgfrb-cre mice expressed higher levels of Acta2 and Col1α1 and were correspondingly more potently activated. In vivo [4-(2-chlorophenyl-4-fluoro-1-piperidinyl][5-(1H-pyrazol-4-yl)-3-thienyl]-methanone administration prior to chemical injury recapitulated findings in Hsd11b1-/- mice, including greater fibrosis. CONCLUSION: 11ßHSD1 deficiency enhances myofibroblast activation and promotes initial fibrosis following chemical liver injury; hence, the effects of 11ßHSD1 inhibitors on liver injury and repair are likely to be context-dependent and deserve careful scrutiny as these compounds are developed for chronic diseases including metabolic syndrome and dementia. (Hepatology 2018;67:2167-2181).


Assuntos
11-beta-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenases/deficiência , Cirrose Hepática/etiologia , Miofibroblastos/fisiologia , Animais , Modelos Animais de Doenças , Hepatócitos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
9.
Gastroenterology ; 153(1): 233-248.e16, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28363640

RESUMO

BACKGROUND & AIMS: There is growing interest in the use of bone marrow cells to treat liver fibrosis, however, little is known about their antifibrotic efficacy or the identity of their effector cell(s). Sphingosine-1-phosphate (S1P) mediates egress of immune cells from the lymphoid organs into the lymphatic vessels; we investigated its role in the response of hematopoietic stem cells (HSCs) to liver fibrosis in mice. METHODS: Purified (c-kit+/sca1+/lin-) HSCs were infused repeatedly into mice undergoing fibrotic liver injury. Chronic liver injury was induced in BoyJ mice by injection of carbon tetrachloride (CCl4) or placement on a methionine-choline-deficient diet. Some mice were irradiated and given transplants of bone marrow cells from C57BL6 mice, with or without the S1P antagonist FTY720; we then studied HSC mobilization and localization. Migration of HSC lines was quantified in Transwell assays. Levels of S1P in liver, bone marrow, and lymph fluid were measured using an enzyme-linked immunosorbent assay. Liver tissues were collected and analyzed by immunohistochemical quantitative polymerase chain reaction and sphingosine kinase activity assays. We performed quantitative polymerase chain reaction analyses of the expression of sphingosine kinase 1 and 2, sphingosine-1-phosphate lyase 1, and sphingosine-1-phosphate phosphatase 1 in normal human liver and cirrhotic liver from patients with alcohol-related liver disease (n = 6). RESULTS: Infusions of HSCs into mice with liver injury reduced liver scarring based on picrosirius red staining (49.7% reduction in mice given HSCs vs control mice; P < .001), and hepatic hydroxyproline content (328 mg/g in mice given HSCs vs 428 mg/g in control mice; P < .01). HSC infusion also reduced hepatic expression of α-smooth muscle actin (0.19 ± 0.007-fold compared with controls; P < .0001) and collagen type I α 1 chain (0.29 ± 0.17-fold compared with controls; P < .0001). These antifibrotic effects were maintained with infusion of lymphoid progenitors that lack myeloid potential and were associated with increased numbers of recipient neutrophils and macrophages in liver. In studies of HSC cell lines, we found HSCs to recruit monocytes, and this process to require C-C motif chemokine receptor 2. In fibrotic liver tissue from mice and patients, hepatic S1P levels increased owing to increased hepatic sphingosine kinase-1 expression, which contributed to a reduced liver:lymph S1P gradient and limited HSC egress from the liver. Mice given the S1P antagonist (FTY720) with HSCs had increased hepatic retention of HSCs (1697 ± 247 cells in mice given FTY720 vs 982 ± 110 cells in controls; P < .05), and further reductions in fibrosis. CONCLUSIONS: In studies of mice with chronic liver injury, we showed the antifibrotic effects of repeated infusions of purified HSCs. We found that HSCs promote recruitment of endogenous macrophages and neutrophils. Strategies to reduce SIP signaling and increase retention of HSCs in the liver could increase their antifibrotic activities and be developed for treatment of patients with liver fibrosis.


Assuntos
Movimento Celular/efeitos dos fármacos , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/fisiologia , Cirrose Hepática/prevenção & controle , Lisofosfolipídeos/antagonistas & inibidores , Lisofosfolipídeos/metabolismo , Esfingosina/análogos & derivados , Actinas/metabolismo , Aldeído Liases/genética , Animais , Linhagem Celular , Doença Hepática Crônica Induzida por Substâncias e Drogas/complicações , Colágeno Tipo I/metabolismo , Cadeia alfa 1 do Colágeno Tipo I , Feminino , Cloridrato de Fingolimode/uso terapêutico , Expressão Gênica , Humanos , Imunossupressores/uso terapêutico , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/etiologia , Cirrose Hepática/genética , Cirrose Hepática/patologia , Linfa/metabolismo , Macrófagos , Masculino , Proteínas de Membrana/genética , Camundongos , Monócitos , Neutrófilos , Monoéster Fosfórico Hidrolases/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Esfingosina/antagonistas & inibidores , Esfingosina/metabolismo
10.
PLoS Med ; 14(2): e1002248, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28245243

RESUMO

BACKGROUND: Chronic liver scarring from any cause leads to cirrhosis, portal hypertension, and a progressive decline in renal blood flow and renal function. Extreme renal vasoconstriction characterizes hepatorenal syndrome, a functional and potentially reversible form of acute kidney injury in patients with advanced cirrhosis, but current therapy with systemic vasoconstrictors is ineffective in a substantial proportion of patients and is limited by ischemic adverse events. Serelaxin (recombinant human relaxin-2) is a peptide molecule with anti-fibrotic and vasoprotective properties that binds to relaxin family peptide receptor-1 (RXFP1) and has been shown to increase renal perfusion in healthy human volunteers. We hypothesized that serelaxin could ameliorate renal vasoconstriction and renal dysfunction in patients with cirrhosis and portal hypertension. METHODS AND FINDINGS: To establish preclinical proof of concept, we developed two independent rat models of cirrhosis that were characterized by progressive reduction in renal blood flow and glomerular filtration rate and showed evidence of renal endothelial dysfunction. We then set out to further explore and validate our hypothesis in a phase 2 randomized open-label parallel-group study in male and female patients with alcohol-related cirrhosis and portal hypertension. Forty patients were randomized 1:1 to treatment with serelaxin intravenous (i.v.) infusion (for 60 min at 80 µg/kg/d and then 60 min at 30 µg/kg/d) or terlipressin (single 2-mg i.v. bolus), and the regional hemodynamic effects were quantified by phase contrast magnetic resonance angiography at baseline and after 120 min. The primary endpoint was the change from baseline in total renal artery blood flow. Therapeutic targeting of renal vasoconstriction with serelaxin in the rat models increased kidney perfusion, oxygenation, and function through reduction in renal vascular resistance, reversal of endothelial dysfunction, and increased activation of the AKT/eNOS/NO signaling pathway in the kidney. In the randomized clinical study, infusion of serelaxin for 120 min increased total renal arterial blood flow by 65% (95% CI 40%, 95%; p < 0.001) from baseline. Administration of serelaxin was safe and well tolerated, with no detrimental effect on systemic blood pressure or hepatic perfusion. The clinical study's main limitations were the relatively small sample size and stable, well-compensated population. CONCLUSIONS: Our mechanistic findings in rat models and exploratory study in human cirrhosis suggest the therapeutic potential of selective renal vasodilation using serelaxin as a new treatment for renal dysfunction in cirrhosis, although further validation in patients with more advanced cirrhosis and renal dysfunction is required. TRIAL REGISTRATION: ClinicalTrials.gov NCT01640964.


Assuntos
Nefropatias/tratamento farmacológico , Rim/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico , Relaxina/farmacologia , Relaxina/uso terapêutico , Adolescente , Adulto , Idoso , Animais , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Rim/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Fluxo Sanguíneo Regional/efeitos dos fármacos , Escócia , Adulto Jovem
11.
Semin Liver Dis ; 35(2): 119-31, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25974898

RESUMO

With evidence from a large number of animal models and clinical trials, it is now beyond debate that liver fibrosis and even cirrhosis are potentially reversible if the underlying cause can be successfully eliminated. However, in a significant proportion of patients cure of the underlying disease may not result in fibrosis regression or a significant reduction of the risk for hepatocellular carcinoma development. Understanding of the mechanistic pathways and regulatory factors that characterize matrix remodeling and architectural repair during fibrosis regression may provide therapeutic approaches to induce or accelerate regression as well as novel diagnostic tools. Recent seminal observations have determined that in resolving liver fibrosis a significant proportion of hepatic stellate cell-myofibroblasts (HSC-MFs) can revert to a near quiescent phenotype. Hepatic macrophages derived from inflammatory monocytes may contribute to fibrosis resolution through an in situ phenotypic switch mediated by phagocytosis. Emerging therapeutic approaches include deletion or inactivation of HSC-MFs, modulation of macrophage activity and autologous cell infusion therapies. Novel noninvasive diagnostic tests such as serum and imaging markers responsive to extracellular matrix degradation are being developed to evaluate the clinical efficacy of antifibrotic interventions.


Assuntos
Células Estreladas do Fígado/patologia , Cirrose Hepática/patologia , Recuperação de Função Fisiológica , Animais , Células Estreladas do Fígado/metabolismo , Humanos , Cirrose Hepática/metabolismo , Transdução de Sinais
12.
Proc Natl Acad Sci U S A ; 109(46): E3186-95, 2012 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-23100531

RESUMO

Although macrophages are widely recognized to have a profibrotic role in inflammation, we have used a highly tractable CCl(4)-induced model of reversible hepatic fibrosis to identify and characterize the macrophage phenotype responsible for tissue remodeling: the hitherto elusive restorative macrophage. This CD11B(hi) F4/80(int) Ly-6C(lo) macrophage subset was most abundant in livers during maximal fibrosis resolution and represented the principle matrix metalloproteinase (MMP) -expressing subset. Depletion of this population in CD11B promoter-diphtheria toxin receptor (CD11B-DTR) transgenic mice caused a failure of scar remodeling. Adoptive transfer and in situ labeling experiments showed that these restorative macrophages derive from recruited Ly-6C(hi) monocytes, a common origin with profibrotic Ly-6C(hi) macrophages, indicative of a phenotypic switch in vivo conferring proresolution properties. Microarray profiling of the Ly-6C(lo) subset, compared with Ly-6C(hi) macrophages, showed a phenotype outside the M1/M2 classification, with increased expression of MMPs, growth factors, and phagocytosis-related genes, including Mmp9, Mmp12, insulin-like growth factor 1 (Igf1), and Glycoprotein (transmembrane) nmb (Gpnmb). Confocal microscopy confirmed the postphagocytic nature of restorative macrophages. Furthermore, the restorative macrophage phenotype was recapitulated in vitro by the phagocytosis of cellular debris with associated activation of the ERK signaling cascade. Critically, induced phagocytic behavior in vivo, through administration of liposomes, increased restorative macrophage number and accelerated fibrosis resolution, offering a therapeutic strategy to this orphan pathological process.


Assuntos
Antígenos Ly/imunologia , Intoxicação por Tetracloreto de Carbono/imunologia , Regulação da Expressão Gênica/imunologia , Cirrose Hepática/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Animais , Antígenos Ly/genética , Antígeno CD11b/genética , Antígeno CD11b/imunologia , Tetracloreto de Carbono/toxicidade , Intoxicação por Tetracloreto de Carbono/genética , Intoxicação por Tetracloreto de Carbono/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/imunologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Cirrose Hepática/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/imunologia , Macrófagos/patologia , Metaloproteinase 12 da Matriz/genética , Metaloproteinase 12 da Matriz/imunologia , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/imunologia , Camundongos , Camundongos Transgênicos , Monócitos/patologia
13.
Trends Pharmacol Sci ; 45(7): 614-627, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38853100

RESUMO

Growing evidence suggests that metabolic dysfunction-associated steatotic liver disease (MASLD) is significantly higher in men versus women. Increased prevalence is observed in postmenopausal women, suggesting that age and sex (hormones) influence MASLD development and progression. Molecular data further reveal that sex regulates the innate immune responses with an essential role in MASLD progression. To date, there has been limited focus on the role of innate immune sexual dimorphism in MASLD, and differences between men and women are not considered in the current drug discovery landscape. In this review, we summarize the sex disparities and innate immune sexual dimorphism in MASLD pathogenesis. We further highlight the importance of harnessing sexual dimorphism in identifying therapeutic targets, developing pharmacological therapies, and designing (pre-) clinical studies for the personalized treatment for MASLD.


Assuntos
Imunidade Inata , Caracteres Sexuais , Humanos , Animais , Feminino , Masculino , Fígado Gorduroso/imunologia , Doenças Metabólicas/imunologia , Doenças Metabólicas/tratamento farmacológico
14.
Cell Rep ; 43(5): 114250, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38762882

RESUMO

Acute stroke triggers extensive changes to myeloid immune cell populations in the brain that may be targets for limiting brain damage and enhancing repair. Immunomodulatory approaches will be most effective with precise manipulation of discrete myeloid cell phenotypes in time and space. Here, we investigate how stroke alters mononuclear myeloid cell composition and phenotypes at single-cell resolution and key spatial patterns. Our results show that multiple reactive microglial states and monocyte-derived populations contribute to an extensive myeloid cell repertoire in post-stroke brains. We identify important overlaps and distinctions among different cell types/states that involve ontogeny- and spatial-related properties. Notably, brain connectivity with infarcted tissue underpins the pattern of local and remote altered cell accumulation and reactivity. Our discoveries suggest a global but anatomically governed brain myeloid cell response to stroke that comprises diverse phenotypes arising through intrinsic cell ontogeny factors interacting with exposure to spatially organized brain damage and neuro-axonal cues.


Assuntos
Encéfalo , Microglia , Células Mieloides , Fenótipo , Acidente Vascular Cerebral , Animais , Encéfalo/patologia , Acidente Vascular Cerebral/patologia , Células Mieloides/metabolismo , Microglia/patologia , Microglia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Monócitos/patologia
16.
Hepatology ; 55(6): 1965-75, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22223197

RESUMO

UNLABELLED: Elastin has been linked to maturity of liver fibrosis. To date, the regulation of elastin secretion and its degradation in liver fibrosis has not been characterized. The aim of this work was to define elastin accumulation and the role of the paradigm elastase macrophage metalloelastase (MMP-12) in its turnover during fibrosis. Liver fibrosis was induced by either intraperitoneal injections of carbon tetrachloride (CCl(4) ) for up to 12 weeks (rat and mouse) or oral administration of thioacetamide (TAA) for 1 year (mouse). Elastin synthesis, deposition, and degradation were investigated by immunohistochemistry, quantitative polymerase chain reaction (qPCR), western blotting, and casein zymography. The regulation of MMP-12 elastin degradation was defined mechanistically using CD11b-DTR and MMP-12 knockout mice. In a CCl(4) model of fibrosis in rat, elastin deposition was significantly increased only in advanced fibrosis. Tropoelastin expression increased with duration of injury. MMP-12 protein levels were only modestly changed and in coimmunoprecipitation experiments MMP-12 was bound in greater quantities to its inhibitor TIMP-1 in advanced versus early fibrosis. Immunohistochemistry and macrophage depletion experiments indicated that macrophages were the sole source of MMP-12. Exposure of CCl(4) in MMP-12(-/-) mice led to a similar degree of overall fibrosis compared to wildtype (WT) but increased perisinusoidal elastin. Conversely, oral administration of TAA caused both higher elastin accumulation and higher fibrosis in MMP-12(-/-) mice compared with WT. CONCLUSION: Elastin is regulated at the level of degradation during liver fibrosis. Macrophage-derived MMP-12 regulates elastin degradation even in progressive experimental liver fibrosis. These observations have important implications for the design of antifibrotic therapies.


Assuntos
Elastina/metabolismo , Cirrose Hepática Experimental/metabolismo , Macrófagos/enzimologia , Metaloproteinase 12 da Matriz/fisiologia , Animais , Tetracloreto de Carbono/toxicidade , Fígado/metabolismo , Metaloproteinase 12 da Matriz/genética , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Inibidor Tecidual de Metaloproteinase-1/genética , Tropoelastina/biossíntese
17.
Nat Med ; 29(11): 2939-2953, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37903863

RESUMO

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the commonest cause of chronic liver disease worldwide and represents an unmet precision medicine challenge. We established a retrospective national cohort of 940 histologically defined patients (55.4% men, 44.6% women; median body mass index 31.3; 32% with type 2 diabetes) covering the complete MASLD severity spectrum, and created a secure, searchable, open resource (SteatoSITE). In 668 cases and 39 controls, we generated hepatic bulk RNA sequencing data and performed differential gene expression and pathway analysis, including exploration of gender-specific differences. A web-based gene browser was also developed. We integrated histopathological assessments, transcriptomic data and 5.67 million days of time-stamped longitudinal electronic health record data to define disease-stage-specific gene expression signatures, pathogenic hepatic cell subpopulations and master regulator networks associated with adverse outcomes in MASLD. We constructed a 15-gene transcriptional risk score to predict future hepatic decompensation events (area under the receiver operating characteristic curve 0.86, 0.81 and 0.83 for 1-, 3- and 5-year risk, respectively). Additionally, thyroid hormone receptor beta regulon activity was identified as a critical suppressor of disease progression. SteatoSITE supports rational biomarker and drug development and facilitates precision medicine approaches for patients with MASLD.


Assuntos
Diabetes Mellitus Tipo 2 , Fígado Gorduroso , Doenças Metabólicas , Masculino , Humanos , Feminino , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Estudos Retrospectivos , Índice de Massa Corporal
18.
J Exp Med ; 220(4)2023 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-36749798

RESUMO

Metastatic castration-resistant prostate cancer (PC) is the final stage of PC that acquires resistance to androgen deprivation therapies (ADT). Despite progresses in understanding of disease mechanisms, the specific contribution of the metastatic microenvironment to ADT resistance remains largely unknown. The current study identified that the macrophage is the major microenvironmental component of bone-metastatic PC in patients. Using a novel in vivo model, we demonstrated that macrophages were critical for enzalutamide resistance through induction of a wound-healing-like response of ECM-receptor gene expression. Mechanistically, macrophages drove resistance through cytokine activin A that induced fibronectin (FN1)-integrin alpha 5 (ITGA5)-tyrosine kinase Src (SRC) signaling cascade in PC cells. This novel mechanism was strongly supported by bioinformatics analysis of patient transcriptomics datasets. Furthermore, macrophage depletion or SRC inhibition using a novel specific inhibitor significantly inhibited resistant growth. Together, our findings elucidated a novel mechanism of macrophage-induced anti-androgen resistance of metastatic PC and a promising therapeutic approach to treat this deadly disease.


Assuntos
Neoplasias Ósseas , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Antagonistas de Androgênios/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Linhagem Celular Tumoral , Macrófagos/metabolismo , Receptores Androgênicos/genética , Nitrilas/uso terapêutico , Microambiente Tumoral
19.
Hepatology ; 53(6): 2003-15, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21433043

RESUMO

UNLABELLED: Clinical studies of bone marrow (BM) cell therapy for liver cirrhosis are under way but the mechanisms of benefit remain undefined. Cells of the monocyte-macrophage lineage have key roles in the development and resolution of liver fibrosis. Therefore, we tested the therapeutic effects of these cells on murine liver fibrosis. Advanced liver fibrosis was induced in female mice by chronic administration of carbon tetrachloride. Unmanipulated, syngeneic macrophages, their specific BM precursors, or unfractionated BM cells were delivered during liver injury. Mediators of inflammation, fibrosis, and regeneration were measured. Donor cells were tracked by sex-mismatch and green fluorescent protein expression. BM-derived macrophage (BMM) delivery resulted in early chemokine up-regulation with hepatic recruitment of endogenous macrophages and neutrophils. These cells delivered matrix metalloproteinases-13 and -9, respectively, into the hepatic scar. The effector cell infiltrate was accompanied by increased levels of the antiinflammatory cytokine interleukin 10. A reduction in hepatic myofibroblasts was followed by reduced fibrosis detected 4 weeks after macrophage infusion. Serum albumin levels were elevated at this time. Up- regulation of the liver progenitor cell mitogen tumor necrosis factor-like weak inducer of apoptosis (TWEAK) preceded expansion of the progenitor cell compartment. Increased expression of colony stimulating factor-1, insulin-like growth factor-1, and vascular endothelial growth factor also followed BMM delivery. In contrast to the effects of differentiated macrophages, liver fibrosis was not significantly altered by the application of macrophage precursors and was exacerbated by whole BM. CONCLUSION: Macrophage cell therapy improves clinically relevant parameters in experimental chronic liver injury. Paracrine signaling to endogenous cells amplifies the effect. The benefits from this single, defined cell type suggest clinical potential.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Cirrose Hepática/fisiopatologia , Cirrose Hepática/terapia , Regeneração Hepática/fisiologia , Fígado/fisiopatologia , Macrófagos/fisiologia , Macrófagos/transplante , Animais , Tetracloreto de Carbono/efeitos adversos , Quimiocinas/metabolismo , Citocina TWEAK , Modelos Animais de Doenças , Feminino , Fator de Crescimento Insulin-Like I/metabolismo , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Testes de Função Hepática , Fator Estimulador de Colônias de Macrófagos/metabolismo , Masculino , Camundongos , Albumina Sérica/metabolismo , Fatores de Necrose Tumoral/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
20.
Am J Respir Crit Care Med ; 184(5): 569-81, 2011 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-21680953

RESUMO

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a devastating disease. Antiinflammatory therapies, including corticosteroids, are of no benefit. The role of monocytes and macrophages is therefore controversial. OBJECTIVES: To define the role of monocytes and macrophages during lung fibrogenesis and resolution, and explore the phenotype of the cells involved. METHODS: We used multiple in vivo depletional strategies, backed up by adoptive transfer techniques. Further studies were performed on samples from patients with IPF. MEASUREMENTS AND MAIN RESULTS: Depletion of lung macrophages during fibrogenesis reduced pulmonary fibrosis as measured by lung collagen (P = 0.0079); fibrosis score (P = 0.0051); and quantitative polymerase chain reaction for surrogate markers of fibrosis Col1 (P = 0.0083) and a-smooth muscle actin (P = 0.0349). There was an associated reduction in markers of the profibrotic alternative macrophage activation phenotype, Ym1 (P = 0.0179), and Arginase 1. The alternative macrophage marker CD163 was expressed on lung macrophages from patients with IPF. Depletion of Ly6Chi circulating monocytes reduced pulmonary fibrosis (P = 0.0052) and the number of Ym1- positive alternatively activated lung macrophages (P = 0.0310). Their adoptive transfer during fibrogenesis exacerbated fibrosis (P = 0.0304); however, adoptively transferred CD45.1 Ly6Chi cells were not found in the lungs of recipient CD45.2 mice. CONCLUSIONS: We demonstrate the importance of circulating monocytes and lung macrophages during pulmonary fibrosis, and emphasize the importance of the alternatively activated macrophage phenotype. We show that Ly6Chi monocytes facilitate the progression of pulmonary fibrosis, but are not obviously engrafted into lungs thereafter. Finally, we provide empirical data to suggest that macrophages may have a resolution-promoting role during the reversible phase of bleomycin-induced pulmonary fibrosis.


Assuntos
Imunidade Celular , Ativação de Macrófagos/imunologia , Macrófagos Alveolares/imunologia , Monócitos/fisiologia , Fibrose Pulmonar/etiologia , Animais , Bleomicina/toxicidade , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Ativação de Macrófagos/genética , Macrófagos Alveolares/patologia , Camundongos , Fenótipo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia
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