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1.
Aging Cell ; 22(3): e13766, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36660875

RESUMEN

The senescence-associated secretory phenotype (SASP) can promote paracrine invasion while suppressing tumour growth, thus generating complex phenotypic outcomes. Likewise, centrosome amplification can induce proliferation arrest yet also facilitate tumour invasion. However, the eventual fate of cells with centrosome amplification remains elusive. Here, we report that centrosome amplification induces a variant of SASP, which constitutes a pathway activating paracrine invasion. The centrosome amplification-induced SASP is non-canonical as it lacks the archetypal detectable DNA damage and prominent NF-κB activation, but involves Rac activation and production of reactive oxygen species. Consequently, it induces hypoxia-inducible factor 1α and associated genes, including pro-migratory factors such as ANGPTL4. Of note, cellular senescence can either induce tumourigenesis through paracrine signalling or conversely suppress tumourigenesis through p53 induction. By analogy, centrosome amplification-induced SASP may therefore be one reason why extra centrosomes promote malignancy in some experimental models but are neutral in others.


Asunto(s)
Neoplasias , Fenotipo Secretor Asociado a la Senescencia , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Neoplasias/patología , Senescencia Celular/genética , Centrosoma/metabolismo , Centrosoma/patología , Carcinogénesis , Fenotipo , FN-kappa B/metabolismo
2.
iScience ; 25(9): 104983, 2022 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-36093061

RESUMEN

Activation of resident macrophages (Mϕ) and hepatic stellate cells is a key event in chronic liver injury. Mice with heme oxygenase-1 (HO-1; Hmox1)-deficient Mϕ (LysM-Cre:Hmox1 flfl ) exhibit increased inflammation, periportal ductular reaction, and liver fibrosis following bile duct ligation (BDL)-induced liver injury and increased pericellular fibrosis in NASH model. RiboTag-based RNA-sequencing profiling of hepatic HO-1-deficient Mϕ revealed dysregulation of multiple genes involved in lipid and amino acid metabolism, regulation of oxidative stress, and extracellular matrix turnover. Among these genes, ligand of numb-protein X1 (LNX1) expression is strongly suppressed in HO-1-deficient Mϕ. Importantly, HO-1 and LNX1 were expressed by hepatic Mϕ in human biliary and nonbiliary end-stage cirrhosis. We found that Notch1 expression, a downstream target of LNX1, was increased in LysM-Cre:Hmox1 flfl mice. In HO-1-deficient Mϕ treated with heme, transient overexpression of LNX1 drives M2-like Mϕ polarization. In summary, we identified LNX1/Notch1 pathway as a downstream target of HO-1 in liver fibrosis.

3.
JCI Insight ; 1(8): e86914, 2016 06 02.
Artículo en Inglés | MEDLINE | ID: mdl-27699269

RESUMEN

Infections are an important cause of morbidity and mortality in patients with decompensated cirrhosis and ascites. Hypothesizing that innate immune dysfunction contributes to susceptibility to infection, we assessed ascitic fluid macrophage phenotype and function. The expression of complement receptor of the immunoglobulin superfamily (CRIg) and CCR2 defined two phenotypically and functionally distinct peritoneal macrophage subpopulations. The proportion of CRIghi macrophages differed between patients and in the same patient over time, and a high proportion of CRIghi macrophages was associated with reduced disease severity (model for end-stage liver disease) score. As compared with CRIglo macrophages, CRIghi macrophages were highly phagocytic and displayed enhanced antimicrobial effector activity. Transcriptional profiling by RNA sequencing and comparison with human macrophage and murine peritoneal macrophage expression signatures highlighted similarities among CRIghi cells, human macrophages, and mouse F4/80hi resident peritoneal macrophages and among CRIglo macrophages, human monocytes, and mouse F4/80lo monocyte-derived peritoneal macrophages. These data suggest that CRIghi and CRIglo macrophages may represent a tissue-resident population and a monocyte-derived population, respectively. In conclusion, ascites fluid macrophage subset distribution and phagocytic capacity is highly variable among patients with chronic liver disease. Regulating the numbers and/or functions of these macrophage populations could provide therapeutic opportunities in cirrhotic patients.


Asunto(s)
Ascitis/fisiopatología , Cirrosis Hepática/fisiopatología , Macrófagos Peritoneales/citología , Receptores de Complemento 3b/metabolismo , Anciano , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Receptores de Complemento
4.
J Leukoc Biol ; 100(1): 155-61, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-26819317

RESUMEN

Differences in human and mouse immune responses may partly reflect species-specific adaptations and can provide important insights into human immunity. In this study, we show that RNF144B, which encodes an E3 ubiquitin ligase, was lipopolysaccharide-inducible in primary human macrophages and in human macrophage-like THP-1 cells. In contrast, Rnf144b was not lipopolysaccharide-inducible in several mouse cell populations, including primary macrophages from C57BL/6 and BALB/c mice and RAW264.7 macrophages. Similarly, Rnf144b was not up-regulated by infection of C57BL/6 mice with Escherichia coli Although the human and mouse RNF144B genes have conserved transcription start sites, cap analysis of gene expression data confirmed that the RNF144B promoter directs transcription in human but not mouse macrophages. The human and mouse RNF144B genes are controlled by highly conserved TATA-containing promoters, but subtle differences in transcription factor binding sites may account for differential regulation. Using gene silencing, we showed that RNF144B is necessary for priming of inflammasome responses in primary human macrophages. Specifically, RNF144B promotes lipopolysaccharide-inducible IL-1b mRNA expression but does not regulate expression of several other lipopolysaccharide-inducible cytokines (e.g., interleukin-10, interferon-γ) or affect expression of inflammasome components or substrates (e.g., procaspase-1, pro-interleukin-18). Our findings thus revealed a species-specific regulatory mechanism for selective inflammasome priming in human macrophages.


Asunto(s)
Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Inflamasomas/metabolismo , Interleucina-1beta/genética , Lipopolisacáridos/farmacología , Macrófagos/metabolismo , Proteínas de la Membrana/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Humanos , Interleucina-1beta/metabolismo , Macrófagos/citología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Regiones Promotoras Genéticas , Activación Transcripcional
5.
Antimicrob Agents Chemother ; 60(3): 1521-9, 2015 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-26711769

RESUMEN

Broad-spectrum histone deacetylase inhibitors (HDACi) are used clinically as anticancer agents, and more isoform-selective HDACi have been sought to modulate other conditions, including chronic inflammatory diseases. Mouse studies suggest that HDACi downregulate immune responses and may compromise host defense. However, their effects on human macrophage antimicrobial responses are largely unknown. Here, we show that overnight pretreatment of human macrophages with HDACi prior to challenge with Salmonella enterica serovar Typhimurium or Escherichia coli results in significantly reduced intramacrophage bacterial loads, which likely reflect the fact that this treatment regime impairs phagocytosis. In contrast, cotreatment of human macrophages with HDACi at the time of bacterial challenge did not impair phagocytosis; instead, HDACi cotreatment actually promoted clearance of intracellular S. Typhimurium and E. coli. Mechanistically, treatment of human macrophages with HDACi at the time of bacterial infection enhanced mitochondrial reactive oxygen species generation by these cells. The capacity of HDACi to promote the clearance of intracellular bacteria from human macrophages was abrogated when cells were pretreated with MitoTracker Red CMXRos, which perturbs mitochondrial function. The HDAC6-selective inhibitor tubastatin A promoted bacterial clearance from human macrophages, whereas the class I HDAC inhibitor MS-275, which inhibits HDAC1 to -3, had no effect on intracellular bacterial loads. These data are consistent with HDAC6 and/or related HDACs constraining mitochondrial reactive oxygen species production from human macrophages during bacterial challenge. Our findings suggest that, whereas long-term HDACi treatment regimes may potentially compromise host defense, selective HDAC inhibitors may have applications in treating acute bacterial infections.


Asunto(s)
Antineoplásicos/farmacología , Escherichia coli/inmunología , Inhibidores de Histona Desacetilasas/farmacología , Macrófagos/inmunología , Mitocondrias/inmunología , Especies Reactivas de Oxígeno/metabolismo , Salmonella typhimurium/inmunología , Carga Bacteriana/efectos de los fármacos , Benzamidas/farmacología , Células Cultivadas , Histona Desacetilasa 6 , Histona Desacetilasas/efectos de los fármacos , Histona Desacetilasas/metabolismo , Humanos , Ácidos Hidroxámicos/farmacología , Indoles/farmacología , Macrófagos/metabolismo , Compuestos Orgánicos/farmacología , Fagocitosis/efectos de los fármacos , Piridinas/farmacología
6.
J Immunol ; 191(8): 4308-16, 2013 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-24043889

RESUMEN

Monocytes and macrophages are important innate immune cells equipped with danger-sensing receptors, including complement and Toll-like receptors. Complement protein C5a, acting via C5aR, is shown in this study to differentially modulate LPS-induced inflammatory responses in primary human monocytes versus macrophages. Whereas C5a enhanced secretion of LPS-induced IL-6 and TNF from primary human monocytes, C5a inhibited these responses while increasing IL-10 secretion in donor-matched human monocyte-derived macrophages differentiated by GM-CSF or M-CSF. Gαi/c-Raf/MEK/ERK signaling induced by C5a was amplified in macrophages but not in monocytes by LPS. Accordingly, the Gαi inhibitor pertussis toxin and MEK inhibitor U0126 blocked C5a inhibition of LPS-induced IL-6 and TNF production from macrophages. This synergy was independent of IL-10, PI3K, p38, JNK, and the differentiating agent. Furthermore, C5a did not inhibit IL-6 production from macrophages induced by other TLR agonists that are selective for Toll/IL-1R domain-containing adapter inducing IFN-ß (polyinosinic-polycytidylic acid) or MyD88 (imiquimod), demonstrating selectivity for C5a regulation of LPS responses. Finally, suppression of proinflammatory cytokines IL-6 and TNF in macrophages did not compromise antimicrobial activity; instead, C5a enhanced clearance of the Gram-negative bacterial pathogen Salmonella enterica serovar Typhimurium from macrophages. C5aR is thus a regulatory switch that modulates TLR4 signaling via the Gαi/c-Raf/MEK/ERK signaling axis in human macrophages but not monocytes. The differential effects of C5a are consistent with amplifying monocyte proinflammatory responses to systemic danger signals, but attenuating macrophage cytokine responses (without compromising microbicidal activity), thereby restraining inflammatory responses to localized infections.


Asunto(s)
Complemento C5a/metabolismo , Macrófagos/metabolismo , Monocitos/metabolismo , Receptores de Complemento/metabolismo , Aminoquinolinas , Butadienos/farmacología , Células Cultivadas , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/antagonistas & inhibidores , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Humanos , Imiquimod , Inflamación/inducido químicamente , Interleucina-10/biosíntesis , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Lipopolisacáridos , Sistema de Señalización de MAP Quinasas/inmunología , Factor Estimulante de Colonias de Macrófagos , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Nitrilos/farmacología , Toxina del Pertussis/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Poli I-C , Proteínas Proto-Oncogénicas c-raf/metabolismo , Receptor de Anafilatoxina C5a , Salmonella typhimurium/inmunología , Receptor Toll-Like 4/metabolismo , Factores de Necrosis Tumoral/metabolismo
7.
Curr Opin Microbiol ; 16(3): 303-10, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23540353

RESUMEN

Ilya Metchnikoff's use of starfish larvae to discover phagocytosis, and Bruno Lemaitre's and Jules Hoffmann's identification of host defence functions for Drosophila Toll provide compelling examples of the utility of model organisms for discovery of human innate immune pathways. Bruce Beutler's mapping of lipopolysaccharide non-responsiveness in C3H/HeJ mice to the Toll-like Receptor 4 gene similarly highlights the power of the mouse as a model. Models have limitations however, and characterising the functional relevance of human innate immune responses not conserved in the mouse presents both a challenge and an opportunity. Here we review differences between human and mouse Toll-like Receptors and inflammasome-forming Nod-like Receptors in repertoire, regulation and function, highlighting the significance of these differences for human innate immunity.


Asunto(s)
Inmunidad Innata , Inflamasomas/inmunología , Proteínas Adaptadoras de Señalización NOD/inmunología , Receptores Toll-Like/inmunología , Animales , Humanos , Ratones , Ratones Endogámicos C3H
8.
Acta Crystallogr D Biol Crystallogr ; 68(Pt 6): 637-48, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22683786

RESUMEN

Fam96a mRNA, which encodes a mammalian DUF59 protein, is enriched in macrophages. Recombinant human Fam96a forms stable monomers and dimers in solution. Crystal structures of these two forms revealed that each adopts a distinct type of domain-swapped dimer, one of which is stabilized by zinc binding. Two hinge loops control Fam96a domain swapping; both are flexible and highly conserved, suggesting that domain swapping may be a common feature of eukaryotic but not bacterial DUF59 proteins. The derived monomer fold of Fam96a diverges from that of bacterial DUF59 counterparts in that the C-terminal region of Fam96a is much longer and is positioned on the opposite side of the N-terminal core fold. The putative metal-binding site of bacterial DUF59 proteins is not conserved in Fam96a, but Fam96a interacts tightly in vitro with Ciao1, the cytosolic iron-assembly protein. Moreover, Fam96a and Ciao1 can be co-immunoprecipitated, suggesting that the interaction also occurs in vivo. Although predicted to have a signal peptide, it is shown that Fam96a is cytoplasmic. The data reveal that eukaryotic DUF59 proteins share intriguing characteristics with amyloidogenic proteins.


Asunto(s)
Proteínas Portadoras/química , Multimerización de Proteína , Animales , Proteínas Portadoras/metabolismo , Cristalografía por Rayos X , Células HeLa , Humanos , Metalochaperonas/metabolismo , Metaloproteínas , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Estructura Cuaternaria de Proteína , Estructura Terciaria de Proteína , ARN Mensajero/metabolismo , Homología Estructural de Proteína
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