RESUMEN
Obesity and diabetes affect more than half a billion individuals worldwide. Interestingly, the two conditions do not always coincide and the molecular determinants of "healthy" versus "unhealthy" obesity remain ill-defined. Chronic metabolic inflammation (metaflammation) is believed to be pivotal. Here, we tested a hypothesized anti-inflammatory role for heme oxygenase-1 (HO-1) in the development of metabolic disease. Surprisingly, in matched biopsies from "healthy" versus insulin-resistant obese subjects we find HO-1 to be among the strongest positive predictors of metabolic disease in humans. We find that hepatocyte and macrophage conditional HO-1 deletion in mice evokes resistance to diet-induced insulin resistance and inflammation, dramatically reducing secondary disease such as steatosis and liver toxicity. Intriguingly, cellular assays show that HO-1 defines prestimulation thresholds for inflammatory skewing and NF-κB amplification in macrophages and for insulin signaling in hepatocytes. These findings identify HO-1 inhibition as a potential therapeutic strategy for metabolic disease.
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Hemo-Oxigenasa 1/metabolismo , Resistencia a la Insulina , Proteínas de la Membrana/metabolismo , Obesidad/complicaciones , Tejido Adiposo/metabolismo , Animales , Dieta Alta en Grasa , Hepatocitos/metabolismo , Humanos , Inflamación/metabolismo , Hígado/metabolismo , Macrófagos/metabolismo , Enfermedades Metabólicas/metabolismo , Enfermedades Metabólicas/fisiopatología , Ratones , Ratones Noqueados , Obesidad/fisiopatología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Hemolysis drives susceptibility to bacterial infections and predicts poor outcome from sepsis. These detrimental effects are commonly considered to be a consequence of heme-iron serving as a nutrient for bacteria. We employed a Gram-negative sepsis model and found that elevated heme levels impaired the control of bacterial proliferation independently of heme-iron acquisition by pathogens. Heme strongly inhibited phagocytosis and the migration of human and mouse phagocytes by disrupting actin cytoskeletal dynamics via activation of the GTP-binding Rho family protein Cdc42 by the guanine nucleotide exchange factor DOCK8. A chemical screening approach revealed that quinine effectively prevented heme effects on the cytoskeleton, restored phagocytosis and improved survival in sepsis. These mechanistic insights provide potential therapeutic targets for patients with sepsis or hemolytic disorders.
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Infecciones por Bacterias Gramnegativas/inmunología , Factores de Intercambio de Guanina Nucleótido/metabolismo , Hemo/metabolismo , Hemólisis/inmunología , Macrófagos/inmunología , Fagocitosis , Sepsis/inmunología , Animales , Antibacterianos/uso terapéutico , Citoesqueleto/metabolismo , Femenino , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Factores de Intercambio de Guanina Nucleótido/genética , Hemo-Oxigenasa 1/genética , Hemólisis/efectos de los fármacos , Humanos , Evasión Inmune , Macrófagos/efectos de los fármacos , Macrófagos/microbiología , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fagocitosis/efectos de los fármacos , Quinina/uso terapéutico , Células RAW 264.7 , Sepsis/tratamiento farmacológico , Proteína de Unión al GTP cdc42/metabolismoRESUMEN
OBJECTIVES: Bone remodelling is a highly dynamic process dependent on the precise coordination of osteoblasts and haematopoietic-cell derived osteoclasts. Changes in core metabolic pathways during osteoclastogenesis, however, are largely unexplored and it is unknown whether and how these processes are involved in bone homeostasis. METHODS: We metabolically and transcriptionally profiled cells during osteoclast and osteoblast generation. Individual gene expression was characterised by quantitative PCR and western blot. Osteoblast function was assessed by Alizarin red staining. immunoresponsive gene 1 (Irg1)-deficient mice were used in various inflammatory or non-inflammatory models of bone loss. Tissue gene expression was analysed by RNA in situ hybridisation. RESULTS: We show that during differentiation preosteoclasts rearrange their tricarboxylic acid cycle, a process crucially depending on both glucose and glutamine. This rearrangement is characterised by the induction of Irg1 and production of itaconate, which accumulates intracellularly and extracellularly. While the IRG1-itaconate axis is dispensable for osteoclast generation in vitro and in vivo, we demonstrate that itaconate stimulates osteoblasts by accelerating osteogenic differentiation in both human and murine cells. This enhanced osteogenic differentiation is accompanied by reduced proliferation and altered metabolism. Additionally, supplementation of itaconate increases bone formation by boosting osteoblast activity in mice. Conversely, Irg1-deficient mice exhibit decreased bone mass and have reduced osteoproliferative lesions in experimental arthritis. CONCLUSION: In summary, we identify itaconate, generated as a result of the metabolic rewiring during osteoclast differentiation, as a previously unrecognised regulator of osteoblasts.
RESUMEN
Many neurodegenerative diseases (NDs) are characterized by the slow spatial spread of toxic protein species in the brain. The toxic proteins can induce neuronal stress, triggering the Unfolded Protein Response (UPR), which slows or stops protein translation and can indirectly reduce the toxic load. However, the UPR may also trigger processes leading to apoptotic cell death and the UPR is implicated in the progression of several NDs. In this paper, we develop a novel mathematical model to describe the spatiotemporal dynamics of the UPR mechanism for prion diseases. Our model is centered around a single neuron, with representative proteins P (healthy) and S (toxic) interacting with heterodimer dynamics (S interacts with P to form two S's). The model takes the form of a coupled system of nonlinear reaction-diffusion equations with a delayed, nonlinear flux for P (delay from the UPR). Through the delay, we find parameter regimes that exhibit oscillations in the P- and S-protein levels. We find that oscillations are more pronounced when the S-clearance rate and S-diffusivity are small in comparison to the P-clearance rate and P-diffusivity, respectively. The oscillations become more pronounced as delays in initiating the UPR increase. We also consider quasi-realistic clinical parameters to understand how possible drug therapies can alter the course of a prion disease. We find that decreasing the production of P, decreasing the recruitment rate, increasing the diffusivity of S, increasing the UPR S-threshold, and increasing the S clearance rate appear to be the most powerful modifications to reduce the mean UPR intensity and potentially moderate the disease progression.
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Conceptos Matemáticos , Modelos Neurológicos , Neuronas , Enfermedades por Prión , Respuesta de Proteína Desplegada , Respuesta de Proteína Desplegada/fisiología , Enfermedades por Prión/metabolismo , Enfermedades por Prión/patología , Enfermedades por Prión/fisiopatología , Neuronas/metabolismo , Humanos , Animales , Dinámicas no Lineales , Simulación por Computador , Priones/metabolismo , Análisis Espacio-Temporal , ApoptosisRESUMEN
BACKGROUND & AIMS: Inflammation, particularly that mediated by bacterial components translocating from the gut to the liver and binding to toll-like receptors (TLRs), is central to cholestatic liver injury. The triggering receptor expressed on myeloid cells-2 (TREM-2) inhibits TLR-mediated signaling and exerts a protective role in hepatocellular injury and carcinogenesis. This study aims to evaluate the role of TREM-2 in cholestasis. METHODS: TREM-2 expression was analyzed in the livers of patients with primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC), and in mouse models of cholestasis. Wild-type (WT) and Trem-2 deficient (Trem-2-/-) mice were subjected to experimental cholestasis and gut sterilization. Primary cultured Kupffer cells were incubated with lipopolysaccharide and/or ursodeoxycholic acid (UDCA) and inflammatory responses were analyzed. RESULTS: TREM-2 expression was upregulated in the livers of patients with PBC or PSC, and in murine models of cholestasis. Compared to WT, the response to bile duct ligation (BDL)-induced obstructive cholestasis or alpha-naphtylisothiocyanate (ANIT)-induced cholestasis was exacerbated in Trem-2-/- mice. This was characterized by enhanced necroptotic cell death, inflammatory responses and biliary expansion. Antibiotic treatment partially abrogated the effects observed in Trem-2-/- mice after BDL. Experimental overexpression of TREM-2 in the liver of WT mice downregulated ANIT-induced IL-33 expression and neutrophil recruitment. UDCA regulated Trem-1 and Trem-2 expression in primary cultured mouse Kupffer cells and dampened inflammatory gene transcription via a TREM-2-dependent mechanism. CONCLUSIONS: TREM-2 acts as a negative regulator of inflammation during cholestasis, representing a novel potential therapeutic target. LAY SUMMARY: Cholestasis (the reduction or cessation of bile flow) causes liver injury. This injury is exacerbated when gut-derived bacterial components interact with receptors (specifically Toll-like receptors or TLRs) on liver-resident immune cells, promoting inflammation. Herein, we show that the anti-inflammatory receptor TREM-2 dampens TLR-mediated signaling and hence protects against cholestasis-induced liver injury. Thus, TREM-2 could be a potential therapeutic target in cholestasis.
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Colestasis , Glicoproteínas de Membrana , Receptores Inmunológicos , Ácido Ursodesoxicólico , Animales , Antibacterianos , Antiinflamatorios , Colestasis/complicaciones , Inflamación , Interleucina-33 , Lipopolisacáridos , Hígado , Glicoproteínas de Membrana/genética , Ratones , Receptores Inmunológicos/genética , Receptor Activador Expresado en Células Mieloides 1 , Ácido Ursodesoxicólico/farmacologíaRESUMEN
BACKGROUND: Pregnancy is a sensitive time for maternal cardiovascular functioning and exposures to arsenic or manganese may adversely affect blood pressure (BP). OBJECTIVES: This study examined the associations between arsenic and manganese exposures and maternal BP measured during pregnancy. Effect modification by pre-pregnancy body mass index (BMI) was evaluated. METHODS: Pregnant women (N = 1522) were recruited for a prospective cohort study in Bangladesh (2008-2011). Exposure to arsenic and manganese was measured in drinking water at <16 weeks gestation and toenails at one-month postpartum. Systolic and diastolic BP were measured monthly. Linear mixed models estimated mean BP and differences in mean BP over gestation for arsenic or manganese exposures and adjusted for covariates. RESULTS: Arsenic levels had an increasing dose-response association with maternal BP after 25 weeks gestation. Effect modification was observed for BMI. Participants with lower BMI (<23 kg/m2) exposed to 50 µg/L arsenic had 2.83 mmHg (95% CI:1.74-3.92) greater mean systolic and 1.96 mmHg (95% CI: 1.02-2.91 mmHg) diastolic BP compared to those exposed to ≤ 1 µg/L arsenic at 40 weeks gestation. Participants with higher BMI (≥23 kg/m2) showed a greater mean systolic BP of 5.72 mmHg (95% CI: 3.18-8.27 mmHg) and diastolic BP change of 6.09 mmHg (95% CI: 4.02-8.16 mmHg) at 40 weeks gestation when exposed to 50 µg/L compared to ≤ 1 µg/L arsenic. Participants with lower BMI exposed to drinking water manganese in the 2nd quartile (181-573 µg/L) had 1.04 mmHg higher mean diastolic BP (95% CI: 0.01-2.07 mmHg) at 40 weeks gestation compared to those in the 1st quartile (0.5-180 µg/L). CONCLUSION: Arsenic exposures during pregnancy were consistently associated with increased average maternal systolic and diastolic BP. The effect of manganese on BP was less consistent.
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Arsénico , Agua Potable , Presión Sanguínea , Femenino , Humanos , Iones , Manganeso , Embarazo , Estudios ProspectivosRESUMEN
OBJECTIVE: Hepatocellular carcinoma (HCC) is a prevalent and aggressive cancer usually arising on a background of chronic liver injury involving inflammatory and hepatic regenerative processes. The triggering receptor expressed on myeloid cells 2 (TREM-2) is predominantly expressed in hepatic non-parenchymal cells and inhibits Toll-like receptor signalling, protecting the liver from various hepatotoxic injuries, yet its role in liver cancer is poorly defined. Here, we investigated the impact of TREM-2 on liver regeneration and hepatocarcinogenesis. DESIGN: TREM-2 expression was analysed in liver tissues of two independent cohorts of patients with HCC and compared with control liver samples. Experimental HCC and liver regeneration models in wild type and Trem-2-/- mice, and in vitro studies with hepatic stellate cells (HSCs) and HCC spheroids were conducted. RESULTS: TREM-2 expression was upregulated in human HCC tissue, in mouse models of liver regeneration and HCC. Trem-2-/- mice developed more liver tumours irrespective of size after diethylnitrosamine (DEN) administration, displayed exacerbated liver damage, inflammation, oxidative stress and hepatocyte proliferation. Administering an antioxidant diet blocked DEN-induced hepatocarcinogenesis in both genotypes. Similarly, Trem-2-/- animals developed more and larger tumours in fibrosis-associated HCC models. Trem-2-/- livers showed increased hepatocyte proliferation and inflammation after partial hepatectomy. Conditioned media from human HSCs overexpressing TREM-2 inhibited human HCC spheroid growth in vitro through attenuated Wnt ligand secretion. CONCLUSION: TREM-2 plays a protective role in hepatocarcinogenesis via different pleiotropic effects, suggesting that TREM-2 agonism should be investigated as it might beneficially impact HCC pathogenesis in a multifactorial manner.
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Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Glicoproteínas de Membrana/genética , Receptores Inmunológicos/genética , Adulto , Anciano , Animales , Carcinogénesis/genética , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular , Dietilnitrosamina , Femenino , Mutación con Ganancia de Función , Expresión Génica , Células Estrelladas Hepáticas/metabolismo , Hepatitis/metabolismo , Hepatocitos/patología , Hepatocitos/fisiología , Humanos , Hígado/metabolismo , Cirrosis Hepática/metabolismo , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/patología , Regeneración Hepática/genética , Regeneración Hepática/fisiología , Macrófagos/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Noqueados , Persona de Mediana Edad , Estrés Oxidativo , Factores Protectores , ARN/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptores Inmunológicos/metabolismo , Esferoides Celulares , Regulación hacia Arriba , Proteínas Wnt/metabolismo , Vía de Señalización Wnt , Proteína Wnt3/metabolismoRESUMEN
Genetic aberrations in the epigenome are rare in pediatric AML, hence expression data in epigenetic regulation and its downstream effect is lacking in childhood AML. Our pilot study screened epigenetic modifiers and its related oncogenic signal transduction pathways concerning clinical outcomes in a small cohort of pediatric AML in KSA. RNA from diagnostic BM biopsies (n = 35) was subjected to expression analysis employing the nCounter Pan-Cancer pathway panel. The patients were dichotomized into low ASXL1 (17/35; 49%) and high ASXL1 (18/35; 51%) groups based on ROC curve analysis. Age, gender, hematological data or molecular risk factors (FLT3 mutation/molecular fusion) exposed no significant differences across these two distinct ASXL1 expression groups (P > 0.05). High ASXL1 expression showed linkage with high expression of other epigenetic modifiers (TET2/EZH2/IDH1&2). Our data showed that high ASXL1 mRNA is interrelated with increased BRCA1 associated protein-1 (BAP1) and its target gene E2F Transcription Factor 1 (E2F1) expression. High ASXL1 expression was associated with high mortality {10/18 (56%) vs. 1/17; (6%) P < 0 .002}. Low ASXL1 expressers showed better OS {740 days vs. 579 days; log-rank P= < 0.023; HR 7.54 (0.98-54.1)}. The association between high ASXL1 expression and epigenetic modifiers is interesting but unexplained and require further investigation. High ASXL1 expression is associated with BAP1 and its target genes. Patients with high ASXL1 expression showed poor OS without any association with a conventional molecular prognostic marker.
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Epigénesis Genética , Perfilación de la Expresión Génica , Regulación Leucémica de la Expresión Génica , Leucemia Mieloide Aguda , Proteínas Represoras , Proteínas Supresoras de Tumor , Ubiquitina Tiolesterasa , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidad , Masculino , Proteínas Represoras/biosíntesis , Proteínas Represoras/genética , Tasa de Supervivencia , Proteínas Supresoras de Tumor/biosíntesis , Proteínas Supresoras de Tumor/genética , Ubiquitina Tiolesterasa/biosíntesis , Ubiquitina Tiolesterasa/genéticaRESUMEN
BACKGROUND: Many populations are exposed to arsenic, lead, and manganese. These metals influence immune function. We evaluated the association between exposure to single and multiple metals, including arsenic, lead, and manganese, to humoral immunity as measured by antibody concentrations to diphtheria and tetanus toxoid among vaccinated Bangladeshi children. Additionally, we examined if this association was potentially mediated by nutritional status. METHODS: Antibody concentrations to diphtheria and tetanus were measured in children's serum at age 5 (n = 502). Household drinking water was sampled to quantify arsenic (W-As) and manganese (W-Mn), whereas lead was measured in blood (B-Pb). Exposure samples were taken during pregnancy, toddlerhood, and early childhood. Multiple linear regression models (MLRs) with single or combined metal predictors were used to determine the association with antibody outcomes. MLR results were transformed to units of percent change in outcome per doubling of exposure to improve interpretability. Structural equation models (SEMs) were used to further assess exposure to metal mixtures. SEMs regressed a latent exposure variable (Metals), informed by all measured metal variables (W-As, W-Mn, and B-Pb), on a latent outcome variable (Antibody), informed by measured antibody variables (diphtheria and tetanus). Weight-for-age z-score (WFA) at age 5 was evaluated as a mediator. RESULTS: Diphtheria antibody was negatively associated with W-As during pregnancy in MLR, but associations were attenuated after adjusting for W-Mn and B-Pb (- 2.9% change in diphtheria antibody per doubling in W-As, 95% confidence interval [CI]: - 7%, 1.5%). Conversely, pregnancy levels of B-Pb were positively associated with tetanus antibody, even after adjusting for W-As and W-Mn (13.3%, 95% CI: 1.7%, 26.3%). Overall, null associations were observed between W-Mn and antibody outcomes. Analysis by SEMs showed that the latent Metals mixture was significantly associated with the latent Antibody outcome (ß = - 0.16, 95% CI: - 0.26, - 0.05), but the Metals variable was characterized by positive and negative loadings of W-As and B-Pb, respectively. Sex-stratified MLR and SEM analyses showed W-As and B-Pb associations were exclusive to females. Mediation by WFA was null, indicating Metals only had direct effects on Antibody. CONCLUSIONS: We observed significant modulation of vaccine antibody concentrations among children with pregnancy and early life exposures to drinking water arsenic and blood lead. We found distinct differences by child sex, as only females were susceptible to metal-related modulations in antibody levels. Weight-for-age, a nutritional status proxy, did not mediate the association between the metal mixture and vaccine antibody.
Asunto(s)
Anticuerpos Antibacterianos/sangre , Toxoide Diftérico/sangre , Exposición a Riesgos Ambientales/análisis , Inmunidad Humoral , Metales/análisis , Estado Nutricional , Toxoide Tetánico/sangre , Arsénico/análisis , Bangladesh , Preescolar , Agua Potable/análisis , Femenino , Humanos , Lactante , Recién Nacido , Plomo/sangre , Masculino , Manganeso/análisis , Metales/sangre , Embarazo , Estudios ProspectivosRESUMEN
OBJECTIVE: Liver injury impacts hepatic inflammation in part via Toll-like receptor (TLR) signalling. Triggering receptor expressed on myeloid cells 2 (TREM-2) modulates TLR4-mediated inflammation in bone marrow (BM)-derived macrophages but its function in liver injury is unknown. Here we hypothesised that the anti-inflammatory effects of TREM-2 on TLR signalling may limit hepatic injury. DESIGN: TREM-2 expression was analysed in livers of humans with various forms of liver injury compared with control individuals. Acute and chronic liver injury models were performed in wild type and Trem-2-/- mice. Primary liver cells from both genotypes of mice were isolated for in vitro experiments. RESULTS: TREM-2 was expressed on non-parenchymal hepatic cells and induced during liver injury in mice and man. Mice lacking TREM-2 exhibited heightened liver damage and inflammation during acute and repetitive carbon tetrachloride and acetaminophen (APAP) intoxication, the latter of which TREM-2 deficiency was remarkably associated with worsened survival. Liver damage in Trem-2-/- mice following chronic injury and APAP challenge was associated with elevated hepatic lipid peroxidation and macrophage content. BM transplantation experiments and cellular reactive oxygen species assays revealed effects of TREM-2 in the context of chronic injury depended on both immune and resident TREM-2 expression. Consistent with effects of TREM-2 on inflammation-associated injury, primary hepatic macrophages and hepatic stellate cells lacking TREM-2 exhibited augmented TLR4-driven proinflammatory responses. CONCLUSION: Our data indicate that by acting as a natural brake on inflammation during hepatocellular injury, TREM-2 is a critical regulator of diverse types of hepatotoxic injury.
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Cirrosis Hepática/metabolismo , Hígado/metabolismo , Glicoproteínas de Membrana/fisiología , Receptores Inmunológicos/fisiología , Acetaminofén , Anciano , Animales , Tetracloruro de Carbono , Estudios de Casos y Controles , Femenino , Células Madre Hematopoyéticas/metabolismo , Hepatocitos/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Macrófagos del Hígado/metabolismo , Peroxidación de Lípido/fisiología , Cirrosis Hepática/etiología , Cirrosis Hepática/inmunología , Cirrosis Hepática Experimental/inmunología , Cirrosis Hepática Experimental/metabolismo , Masculino , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Ratones Noqueados , Persona de Mediana Edad , Especies Reactivas de Oxígeno/metabolismo , Receptores Inmunológicos/deficiencia , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Receptor Toll-Like 4/fisiología , Regulación hacia Arriba/fisiologíaRESUMEN
CONTEXT: Public Health Ontario (PHO) publishes various infectious disease surveillance reports, but none have yet been formally evaluated. OBJECTIVE: PHO evaluated its monthly and annual infectious disease surveillance reports to assess public health stakeholders' current perception of the products and to develop recommendations for improving future products. DESIGN: An evaluation consisting of an online survey and a review of public Web sites of other jurisdictions with similar annual reports. SETTING: For the online survey, stakeholder organizations targeted were the 36 local public health units and the Health health ministry in Ontario, Canada. PARTICIPANTS: Survey participants included epidemiologists, managers, directors, and other public health practitioners from participating organizations. MAIN OUTCOME MEASURES: Online survey respondents' awareness and access to the reports, their rated usefulness of reports and subsections, and suggestions for improving usefulness; timeliness of select annual reports from other jurisdictions based on the period from data described to report publication. RESULTS: Among 57 survey respondents, between 74% and 97% rated each report as useful; the most common use was for situational awareness. Respondents ranked timeliness as the most important attribute of surveillance reports, followed by data completeness. Among 6 annual reports reviewed, the median time to publication was 11.5 months compared with 23.2 months for PHO. CONCLUSION: Recommendations based on this evaluation have already been applied to the monthly report (eg, focusing on the most useful sections) and have become key considerations when developing future annual reports and other surveillance reporting tools (eg, need to provide more timely reports). Other public health organizations may also use this evaluation to inform aspects of their surveillance report development and evaluation. The evaluation results have provided PHO with direction on how to improve its provincial infectious disease surveillance reporting moving forward, and formed a basis for future work in surveillance product development and evaluation.
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Vigilancia de la Población/métodos , Salud Pública/normas , Notificación de Enfermedades/métodos , Notificación de Enfermedades/normas , Humanos , Ontario , Encuestas y CuestionariosRESUMEN
Phagocytosis and inflammation within the lungs is crucial for host defense during bacterial pneumonia. Triggering receptor expressed on myeloid cells (TREM)-2 was proposed to negatively regulate TLR-mediated responses and enhance phagocytosis by macrophages, but the role of TREM-2 in respiratory tract infections is unknown. Here, we established the presence of TREM-2 on alveolar macrophages (AM) and explored the function of TREM-2 in the innate immune response to pneumococcal infection in vivo. Unexpectedly, we found Trem-2(-/-) AM to display augmented bacterial phagocytosis in vitro and in vivo compared to WT AM. Mechanistically, we detected that in the absence of TREM-2, pulmonary macrophages selectively produced elevated complement component 1q (C1q) levels. We found that these increased C1q levels depended on peroxisome proliferator-activated receptor-δ (PPAR-δ) activity and were responsible for the enhanced phagocytosis of bacteria. Upon infection with S. pneumoniae, Trem-2(-/-) mice exhibited an augmented bacterial clearance from lungs, decreased bacteremia and improved survival compared to their WT counterparts. This work is the first to disclose a role for TREM-2 in clinically relevant respiratory tract infections and demonstrates a previously unknown link between TREM-2 and opsonin production within the lungs.
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Complemento C1q/metabolismo , Modelos Animales de Enfermedad , Pulmón/inmunología , Macrófagos Alveolares/inmunología , Glicoproteínas de Membrana/metabolismo , Neumonía Neumocócica/inmunología , Receptores Inmunológicos/metabolismo , Mucosa Respiratoria/inmunología , Animales , Apoptosis , Línea Celular Transformada , Células Cultivadas , Complemento C1q/genética , Citocinas/metabolismo , Femenino , Pulmón/citología , Pulmón/metabolismo , Pulmón/patología , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patología , Masculino , Glicoproteínas de Membrana/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Infiltración Neutrófila , PPAR gamma/metabolismo , Fagocitosis , Neumonía Neumocócica/metabolismo , Neumonía Neumocócica/patología , Receptores Inmunológicos/genética , Mucosa Respiratoria/citología , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/patología , Análisis de SupervivenciaRESUMEN
During infections, TLR-mediated responses require tight regulation to allow for pathogen removal, while preventing overwhelming inflammation and immunopathology. The triggering receptor expressed on myeloid cells (TREM)-2 negatively regulates inflammation by macrophages and impacts on phagocytosis, but the function of endogenous TREM-2 during infections is poorly understood. We investigated TREM-2's role in regulating TLR4-mediated inflammation by studying wild-type and TREM-2(-/-) mice challenged with LPS and found TREM-2 to dampen early inflammation. Augmented early inflammation in TREM-2(-/-) animals was followed by an accelerated resolution and ultimately improved survival, associated with the induction of the negative regulator A20. Upon infection with Escherichia coli, the otherwise beneficial effect of an exaggerated early immune response in TREM-2(-/-) animals was counteracted by a 50% reduction in bacterial phagocytosis. In line with this, TREM-2(-/-) peritoneal macrophages (PMs) exhibited augmented inflammation following TLR4 stimulation, demonstrating the presence and negative regulatory functionality of TREM-2 on primary PMs. Significantly, we identified a high turnover rate because TREM-2 RNA is 25-fold down-regulated and the protein proteasomally degraded upon LPS encounter, thus ensuring a tightly regulated and versatile system that modulates inflammation. Our results illustrate TREM-2's effects on infection-triggered inflammation and identify TREM-2 as a potential target to prevent overwhelming inflammation while preserving antibacterial-effector functions.
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Infecciones por Bacterias Gramnegativas/inmunología , Glicoproteínas de Membrana/metabolismo , Receptores Inmunológicos/metabolismo , Sepsis/inmunología , Animales , Carga Bacteriana , Regulación hacia Abajo , Endotoxemia/etiología , Endotoxemia/inmunología , Infecciones por Escherichia coli/etiología , Infecciones por Escherichia coli/inmunología , Infecciones por Escherichia coli/microbiología , Femenino , Infecciones por Bacterias Gramnegativas/etiología , Infecciones por Bacterias Gramnegativas/microbiología , Mediadores de Inflamación/metabolismo , Lipopolisacáridos/toxicidad , Macrófagos Peritoneales/inmunología , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Peritonitis/etiología , Peritonitis/inmunología , Peritonitis/microbiología , Fagocitosis , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Inmunológicos/deficiencia , Receptores Inmunológicos/genética , Sepsis/etiología , Receptor Toll-Like 4/metabolismoRESUMEN
Oxidized phospholipids (OxPL) were originally discovered as by-products and mediators of chronic inflammation such as in atherosclerosis. Over the last years, an increasing body of evidence led to the notion that OxPL not only contribute to the pathogenesis of chronic inflammatory processes but in addition play an integral role as modulators of inflammation during acute infections. Thereby, host defense mechanisms involve the generation of oxygen radicals that oxidize ubiquitously present phospholipids, which in turn act as danger-associated molecular patterns (DAMPs). These OxPL-derived DAMPs can exhibit both pro- and anti-inflammatory functions that ultimately alter the host response to pathogens. In this review, we summarize the currently available data on the role of OxPL in infectious diseases.
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Infecciones Bacterianas/metabolismo , Inflamación/metabolismo , Fosfolípidos/metabolismo , Virosis/metabolismo , Animales , Infecciones Bacterianas/inmunología , Humanos , Inflamación/inmunología , Oxidación-Reducción , Peritonitis/inmunología , Peritonitis/metabolismo , Peritonitis/microbiología , Fosfolípidos/análisis , Fosfolípidos/inmunología , Especies Reactivas de Oxígeno/inmunología , Especies Reactivas de Oxígeno/metabolismo , Virosis/inmunologíaRESUMEN
CD36 is a scavenger receptor that exhibits pleiotropic functions, including adhesion to thrombospondin, inhibition of angiogenesis, transport of long-chain fatty acids, and clearance of apoptotic cells. In addition, it has been implicated in the host immune response because it acts as a coreceptor for TLR2 and plays a role in Staphylococcus aureus infection. However, its role in other Gram-positive bacterial infections is unclear. In this study, using mice deficient in CD36, we sought to examine the role of CD36 in pneumococcal pneumonia, a major cause of morbidity and mortality worldwide. We show that CD36 is expressed on both alveolar macrophages and respiratory epithelial cells. Early in infection, CD36(-/-) mice have an exaggerated inflammatory response compared with wild-type littermate controls. In vitro studies using CD36(-/-) primary cells confirm the enhanced early inflammation in response to S. pneumoniae and its lipoteichoic acid, demonstrate that S. pneumoniae binds to cells via its phosphocholine residues, and suggest a role for CD36 in reducing inflammation induced by the phosphocholine residues of pneumococcal lipoteichoic acid. Later in infection, although CD36(-/-) mice exhibit impaired bacterial clearance, owing to a decreased capacity of CD36(-/-) macrophages to phagocytose S. pneumoniae, minor effects on mortality occur, in comparison with those in wild-type littermate control mice. These data show that CD36 contributes to the pulmonary host response during S. pneumoniae infection by virtue of its ability to act as a phagocytic receptor and as a modulator of the early innate immune response.
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Antígenos CD36/metabolismo , Fagocitosis/inmunología , Neumonía Neumocócica/inmunología , Neumonía Neumocócica/metabolismo , Streptococcus pneumoniae/inmunología , Animales , Antígenos CD36/genética , Modelos Animales de Enfermedad , Femenino , Inmunidad Innata , Inflamación/inmunología , Inflamación/metabolismo , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/metabolismo , Ratones , Ratones Noqueados , Fosforilcolina/inmunología , Neumonía Neumocócica/genética , Neumonía Neumocócica/mortalidad , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/microbiología , Streptococcus pneumoniae/químicaRESUMEN
Introduction Obesity is a pandemic causing a significant burden on healthcare systems and carries increased morbidity and mortality. One of the options for managing obesity is endoscopic intragastric balloon (IGB) insertion. The aim of the study is to assess the efficacy, tolerance, and side effects of IGB insertion in overweight and obese patients. Methods This is a cross-sectional retrospective study that includes 71 patients who underwent IGB insertion from 2015 to 2019 at King Hamad University Hospital (KHUH), Kingdom of Bahrain. Records of these patients were accessed to assess the percentage of weight loss at the time of balloon removal, complications, and tolerance of the procedure. Furthermore, telephonic interviews were conducted to enquire about side effects and the satisfaction of the procedure. Results A total of 57 patients were included in the weight loss analysis. Thirteen patients did not tolerate the balloon, and one patient had a balloon rupture. The patients experienced a significant reduction in weight upon balloon removal with a mean of 9.74 ± 8.71 kg (p-value of <0.001) and percentage total body weight loss of 10.48 ± 8.07 (p-value of <0.001). A significant reduction was also seen in the body mass index of 3.67 ± 3.57 (p-value of <0.001). The most frequent side effects were nausea, vomiting, and abdominal pain. No major complications or mortalities occurred. Conclusion Intragastric balloons are effective in establishing weight loss. Among patients who tolerated the procedure, the most frequently reported side effects were nausea, vomiting, and abdominal pain.
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Mucosal-associated lymphoid tissue (MALT) is a low-grade lymphoma derived from marginal zone B cells in extranodal tissue. Gastric MALT lymphoma is frequently seen; however, duodenal MALT lymphoma is rare, and there is no standardized knowledge up to date about the management of the disease. We present a case of a 56-year-old woman with gastric and duodenal MALT lymphoma.
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Signal transducer and activator of transcription 3 (STAT3) is frequently overexpressed in patients with acute myeloid leukemia (AML). STAT3 exists in two distinct alternatively spliced isoforms, the full-length isoform STAT3α and the C-terminally truncated isoform STAT3ß. While STAT3α is predominantly described as an oncogenic driver, STAT3ß has been suggested to act as a tumor suppressor. To elucidate the role of STAT3ß in AML, we established a mouse model of STAT3ß-deficient, MLL-AF9-driven AML. STAT3ß deficiency significantly shortened survival of leukemic mice confirming its role as a tumor suppressor. Furthermore, RNA sequencing revealed enhanced STAT1 expression and interferon (IFN) signaling upon loss of STAT3ß. Accordingly, STAT3ß-deficient leukemia cells displayed enhanced sensitivity to blockade of IFN signaling through both an IFNAR1 blocking antibody and the JAK1/2 inhibitor Ruxolitinib. Analysis of human AML patient samples confirmed that elevated expression of IFN-inducible genes correlated with poor overall survival and low STAT3ß expression. Together, our data corroborate the tumor suppressive role of STAT3ß in a mouse model in vivo. Moreover, they provide evidence that its tumor suppressive function is linked to repression of the STAT1-mediated IFN response. These findings suggest that the STAT3ß/α mRNA ratio is a significant prognostic marker in AML and holds crucial information for targeted treatment approaches. Patients displaying a low STAT3ß/α mRNA ratio and unfavorable prognosis could benefit from therapeutic interventions directed at STAT1/IFN signaling.
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Leucemia Mieloide Aguda , Factor de Transcripción STAT3 , Animales , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/metabolismo , Humanos , Factor de Transcripción STAT3/metabolismo , Ratones , Transducción de Señal , Interferones/metabolismo , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT1/genética , Ratones Endogámicos C57BL , Receptor de Interferón alfa y beta/metabolismo , Receptor de Interferón alfa y beta/genética , Línea Celular Tumoral , Nitrilos , Pirazoles , PirimidinasRESUMEN
BACKGROUND & AIMS: Reported HBV drug resistance mutations among previously untreated patients with chronic hepatitis B are variable. Whether resistant HBV strains are transmitted in the acute setting is uncertain. We sought to document the presence of antiviral resistance (AVR) mutations in patients with acute HBV (AHB) infection. METHODS: AHB infection was defined by HBsAg/IgM anti-HBc positivity, ALT>10X ULN and compatible clinical history. The TRUGENE HBV kit was used to perform genotyping and direct sequencing of the viral polymerase. INNO-LiPA HBV DRv2 and DRv3 were used to detect AVR mutations. Clonal sequencing was conducted on selected specimens. RESULTS: Twenty-three patients were evaluated (mean age, 43 years; 54% male; 39% African American, 39% Caucasian, 13% Hispanic and 4% Asian). The mean peak ALT was 1554.2IU/L and mean peak total serum bilirubin was 12 mg/dl. The HBV DNA median viral load (N = 15) was 5.14 log(10)IU/ml. Nineteen patients were genotype A, and 1 each were genotype C, D, E and G. HBV drug resistance mutations were not detected by direct sequencing or INNO-LiPA. Clonal sequencing was conducted on 192 clones isolated from three patients and showed rtA181T, rtM250V and rtS202G mutations at an overall frequency of 1.54%, 1.39%, and 1.67% respectively. CONCLUSIONS: We detected adefovir/lamivudine and entecavir relevant mutations in a minor population (<2%) of viral clones by clonal sequencing only. The clinical significance of these mutations is uncertain and may represent small populations of quasi-species vs. transmission of drug resistant strains.
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Antivirales/uso terapéutico , Farmacorresistencia Viral/genética , Hepatitis B/tratamiento farmacológico , Hepatitis B/genética , Mutación/genética , Enfermedad Aguda , Adenina/análogos & derivados , Adenina/uso terapéutico , Adulto , Estudios de Cohortes , Estudios Transversales , Femenino , Genotipo , Guanina/análogos & derivados , Guanina/uso terapéutico , Hepatitis B/epidemiología , Humanos , Lamivudine/uso terapéutico , Masculino , Organofosfonatos/uso terapéutico , Estudios Retrospectivos , Análisis de Secuencia de ADN , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: The incidence of acute hepatitis B virus (HBV) infection in the United States is declining, and precise epidemiology for newly acquired infection remains obscure. GOALS: We sought to clarify the clinical presentation and management of acute symptomatic HBV infection at a hepatology referral center. STUDY: We prospectively evaluated the demographic, epidemiological, clinical, and treatment data of 32 patients with acute symptomatic HBV who were referred to a single urban tertiary care hospital in the United States. RESULTS: Slightly more than half of the patients were male (53%) or belonged to the black race (53%) and slightly fewer than half of the patients (47%) were unemployed. The median patient age was 41.9 years, and 20 (63%) patients were unmarried. The most common HBV risk factor was a new sexual partner over the previous months (34%). Fifteen percent of the patients reported no known risk factors. Four (13%) patients were diabetic. Presenting symptoms included jaundice (75%), abdominal pain (63%), and marked fatigue (59%). The mean peak for aspartate aminotransferase/alanine aminotransferase was 1822/2109 IU/L, for total bilirubin was 12.6 mg/dL, and for International Normalized Ratio was 1.53. Eight patients (25%) were started on oral nucleot(s)ide therapy. One diabetic patient underwent liver transplantation. CONCLUSIONS: In a sample of patients from a US urban tertiary hepatology center, common epidemiological features of acute symptomatic hepatitis B were being middle aged and unmarried and having acquired the infection through a new sexual contact. Antiviral therapy was sometimes but not commonly started. These data reinforce the need for HBV vaccination of individuals at risk, including those not traditionally targeted.