RESUMO
Several classes of antibiotics have long been known to have beneficial effects that cannot be explained strictly on the basis of their capacity to control the infectious agent. Here, we report that tetracycline antibiotics, which target the mitoribosome, protected against sepsis without affecting the pathogen load. Mechanistically, we found that mitochondrial inhibition of protein synthesis perturbed the electron transport chain (ETC) decreasing tissue damage in the lung and increasing fatty acid oxidation and glucocorticoid sensitivity in the liver. Using a liver-specific partial and acute deletion of Crif1, a critical mitoribosomal component for protein synthesis, we found that mice were protected against sepsis, an observation that was phenocopied by the transient inhibition of complex I of the ETC by phenformin. Together, we demonstrate that mitoribosome-targeting antibiotics are beneficial beyond their antibacterial activity and that mitochondrial protein synthesis inhibition leading to ETC perturbation is a mechanism for the induction of disease tolerance.
Assuntos
Antibacterianos/uso terapêutico , Doxiciclina/uso terapêutico , Fígado/imunologia , Pulmão/imunologia , Mitocôndrias/metabolismo , Sepse/tratamento farmacológico , Tetraciclina/uso terapêutico , Animais , Proteínas de Ciclo Celular/genética , Modelos Animais de Doenças , Transporte de Elétrons , Células Hep G2 , Humanos , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
BACKGROUND: Cluster headache is a primary headache disorder characterized by bouts with circadian and circannual patterns. The CLOCK gene has a central role in regulating circadian rhythms. Here, we investigate the circannual CLOCK expression in a population of cluster headache patients in comparison to matched controls. METHODS: Patients with cluster headache were sampled two to four times over at least one year, both in or outside bouts, one week after each solstice and equinox. The expression of CLOCK was measured by quantitative real-time polymerase chain reaction (RT-PCR) in the peripheral blood. RESULTS: This study included 50 patients and 58 matched controls. Among the patient population, composed of 42/50 males (84%) with an average age of 44.6 years, 45/50 (90%) suffered from episodic cluster headache. Two to four samples were collected from each patient adding up to 161 samples, 36 (22.3%) of which were collected within a bout. CLOCK expression for cluster headache patients was considerably different from that of the control population in winter (p-value mean = 0.006283), spring (p-value mean = 0.000006) and summer (p-value mean = 0.000064), but not in autumn (p-value mean = 0.262272). For each season transition, the variations in CLOCK expression were more pronounced in the control group than in the cluster headache population. No statistically significant differences were found between bout and non-bout samples. No individual factors (age, sex, circadian chronotype, smoking and coffee habits or history of migraine) were related to CLOCK expression. CONCLUSIONS: We observed that CLOCK expression in cluster headache patients fluctuates less throughout the year than in the control population. Bout activity and lifestyle factors do not seem to influence CLOCK expression.
Assuntos
Proteínas CLOCK , Cefaleia Histamínica , Humanos , Cefaleia Histamínica/genética , Masculino , Feminino , Adulto , Proteínas CLOCK/genética , Proteínas CLOCK/biossíntese , Pessoa de Meia-Idade , Ritmo Circadiano , Estações do AnoRESUMO
An acute increase in the circulating concentration of glucocorticoid hormones is essential for the survival of severe somatic stresses. Circulating concentrations of GDF15, a hormone that acts in the brain to reduce food intake, are frequently elevated in stressful states. We now report that GDF15 potently activates the hypothalamic-pituitary-adrenal (HPA) axis in mice and rats. A blocking antibody to the GDNF-family receptor α-like receptor completely prevented the corticosterone response to GDF15 administration. In wild-type mice exposed to a range of stressful stimuli, circulating levels of both corticosterone and GDF15 rose acutely. In the case of Escherichia coli or lipopolysaccharide injections, the vigorous proinflammatory cytokine response elicited was sufficient to produce a near-maximal HPA response, regardless of the presence or absence of GDF15. In contrast, the activation of the HPA axis seen in wild-type mice in response to the administration of genotoxic or endoplasmic reticulum toxins, which do not provoke a marked rise in cytokines, was absent in Gdf15-/- mice. In conclusion, consistent with its proposed role as a sentinel hormone, endogenous GDF15 is required for the activation of the protective HPA response to toxins that do not induce a substantial cytokine response. In the context of efforts to develop GDF15 as an antiobesity therapeutic, these findings identify a biomarker of target engagement and a previously unrecognized pharmacodynamic effect, which will require monitoring in human studies.
Assuntos
Fator 15 de Diferenciação de Crescimento/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Animais , Cisplatino/administração & dosagem , Cisplatino/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Glucocorticoides/metabolismo , Fator 15 de Diferenciação de Crescimento/administração & dosagem , Humanos , Lipopolissacarídeos , Camundongos , Ratos , Tunicamicina/farmacologiaRESUMO
Alternative polyadenylation in the 3' UTR (3' UTR-APA) is a mode of gene expression regulation, fundamental for mRNA stability, translation and localization. In the immune system, it was shown that upon T cell activation, there is an increase in the relative expression of mRNA isoforms with short 3' UTRs resulting from 3' UTR-APA. However, the functional significance of 3' UTR-APA remains largely unknown. Here, we studied the physiological function of 3' UTR-APA in the regulation of Myeloid Cell Leukemia 1 (MCL1), an anti-apoptotic member of the Bcl-2 family essential for T cell survival. We found that T cells produce two MCL1 mRNA isoforms (pA1 and pA2) by 3' UTR-APA. We show that upon T cell activation, there is an increase in both the shorter pA1 mRNA isoform and MCL1 protein levels. Moreover, the less efficiently translated pA2 isoform is downregulated by miR-17, which is also more expressed upon T cell activation. Therefore, by increasing the expression of the more efficiently translated pA1 mRNA isoform, which escapes regulation by miR-17, 3' UTR-APA fine tunes MCL1 protein levels, critical for activated T cells' survival. Furthermore, using CRISPR/Cas9-edited cells, we show that depletion of either pA1 or pA2 mRNA isoforms causes severe defects in mitochondria morphology, increases apoptosis and impacts cell proliferation. Collectively, our results show that MCL1 alternative polyadenylation has a key role in the regulation of MCL1 protein levels upon T cell activation and reveal an essential function for MCL1 3' UTR-APA in cell viability and mitochondria dynamics.
Assuntos
Ativação Linfocitária , MicroRNAs/metabolismo , Mitocôndrias/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Poliadenilação , Linfócitos T/metabolismo , Sobrevivência Celular , Humanos , Células Jurkat , Isoformas de RNA , Linfócitos T/fisiologiaRESUMO
Sepsis is a life-threatening organ dysfunction condition caused by a dysregulated host response to an infection. Here we report that the circulating levels of growth and differentiation factor-15 (GDF15) are strongly increased in septic shock patients and correlate with mortality. In mice, we find that peptidoglycan is a potent ligand that signals through the TLR2-Myd88 axis for the secretion of GDF15, and that Gdf15-deficient mice are protected against abdominal sepsis due to increased chemokine CXC ligand 5 (CXCL5)-mediated recruitment of neutrophils into the peritoneum, leading to better local bacterial control. Our results identify GDF15 as a potential target to improve sepsis treatment. Its inhibition should increase neutrophil recruitment to the site of infection and consequently lead to better pathogen control and clearance.
Assuntos
Bacteriemia/imunologia , Quimiocina CXCL5/imunologia , Fator 15 de Diferenciação de Crescimento/imunologia , Neutrófilos/imunologia , Animais , Bacteriemia/genética , Bacteriemia/microbiologia , Bacteriemia/prevenção & controle , Quimiocina CXCL5/genética , Feminino , Fator 15 de Diferenciação de Crescimento/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infiltração de Neutrófilos , Cavidade Peritoneal/microbiologiaRESUMO
Severe sepsis remains a poorly understood systemic inflammatory condition with high mortality rates and limited therapeutic options in addition to organ support measures. Here we show that the clinically approved group of anthracyclines acts therapeutically at a low dose regimen to confer robust protection against severe sepsis in mice. This salutary effect is strictly dependent on the activation of DNA damage response and autophagy pathways in the lung, as demonstrated by deletion of the ataxia telangiectasia mutated (Atm) or the autophagy-related protein 7 (Atg7) specifically in this organ. The protective effect of anthracyclines occurs irrespectively of pathogen burden, conferring disease tolerance to severe sepsis. These findings demonstrate that DNA damage responses, including the ATM and Fanconi Anemia pathways, are important modulators of immune responses and might be exploited to confer protection to inflammation-driven conditions, including severe sepsis.
Assuntos
Antraciclinas/farmacologia , Antibacterianos/farmacologia , Reparo do DNA/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Peritonite/tratamento farmacológico , Sepse/prevenção & controle , Infecções por Adenoviridae/imunologia , Animais , Antraciclinas/uso terapêutico , Antibacterianos/uso terapêutico , Proteínas Mutadas de Ataxia Telangiectasia/deficiência , Proteínas Mutadas de Ataxia Telangiectasia/fisiologia , Proteína 7 Relacionada à Autofagia , Ceco/lesões , Dano ao DNA , Epirubicina/administração & dosagem , Epirubicina/farmacologia , Epirubicina/uso terapêutico , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/fisiologia , Inflamação , Mediadores da Inflamação/análise , Injeções Intraperitoneais , Pulmão/metabolismo , Meropeném , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/deficiência , Proteínas Associadas aos Microtúbulos/fisiologia , Especificidade de Órgãos , Peritonite/etiologia , Peritonite/genética , Peritonite/imunologia , Peritonite/fisiopatologia , Infecções Respiratórias/imunologia , Choque Séptico/prevenção & controle , Tienamicinas/uso terapêutico , Irradiação Corporal TotalRESUMO
Epigenetic marks such as posttranslational histone modifications specify the functional states of underlying DNA sequences, though how they are maintained after their disruption during DNA replication remains a critical question. We identify the mammalian SWI/SNF-like protein SMARCAD1 as a key factor required for the re-establishment of repressive chromatin. The ATPase activity of SMARCAD1 is necessary for global deacetylation of histones H3/H4. In this way, SMARCAD1 promotes methylation of H3K9, the establishment of heterochromatin, and faithful chromosome segregation. SMARCAD1 associates with transcriptional repressors including KAP1, histone deacetylases HDAC1/2 and the histone methyltransferase G9a/GLP and modulates the interaction of HDAC1 and KAP1 with heterochromatin. SMARCAD1 directly interacts with PCNA, a central component of the replication machinery, and is recruited to sites of DNA replication. Our findings suggest that chromatin remodeling by SMARCAD1 ensures that silenced loci, such as pericentric heterochromatin, are correctly perpetuated.
Assuntos
Cromatina/metabolismo , DNA Helicases/metabolismo , Replicação do DNA , Histonas/metabolismo , Acetilação , Adenosina Trifosfatases/metabolismo , Animais , Western Blotting , Linhagem Celular , Células Cultivadas , Cromatina/genética , DNA Helicases/genética , Regulação da Expressão Gênica , Células HEK293 , Células HeLa , Heterocromatina/genética , Heterocromatina/metabolismo , Histona Desacetilase 1/metabolismo , Histona Metiltransferases , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Metilação , Camundongos , Células NIH 3T3 , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ligação Proteica , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fase SRESUMO
Acute appendicitis is the most frequent surgical abdominal emergency, but its etiology remains poorly understood. Histological examination of the appendix, following its removal due to acute appendicitis, consistently shows features in common with bronchial asthma, suggesting an allergic reaction as a candidate etiologic factor. Here, we propose the concept of appendicular lavage and use it to study the levels of the Th2 cytokines IL-4, IL-5, and IL-9 in patients with a clinical diagnosis of acute appendicitis. The study group included 20 patients with a histological diagnosis of phlegmonous appendicitis, 13 patients with gangrenous appendicitis, and a control group of 8 patients with a clinical diagnosis of appendicitis but with normal histology. Cytokine levels were higher in acute appendicitis. The difference was more pronounced when comparing phlegmonous appendicitis with nonpathological appendicitis (p = 0.01) for IL-4 (48.3 vs. 21.3 pg/mL), IL-5 (29.2 vs. 8.0 pg/mL), and IL-9 (34.1 vs. 16.6 pg/mL). This Th2 cytokine profile is compatible with the hypothesis of allergy as an etiologic factor for acute appendicitis and may have important implications for the diagnosis, prevention, and treatment of this condition.
Assuntos
Apendicite/etiologia , Apendicite/metabolismo , Citocinas/metabolismo , Hipersensibilidade/complicações , Hipersensibilidade/metabolismo , Células Th2/metabolismo , Doença Aguda , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
The premessenger RNA of the majority of human genes can generate various transcripts through alternative splicing, and different tissues or disease states show specific patterns of splicing variants. These patterns depend on the relative concentrations of the splicing factors present in the cell nucleus, either as a consequence of their expression levels or of post-translational modifications, such as protein phosphorylation, which are determined by signal transduction pathways. Here, we analyzed the contribution of protein kinases to the regulation of alternative splicing variant Rac1b that is overexpressed in certain tumor types. In colorectal cells, we found that depletion of AKT2, AKT3, GSK3ß, and SRPK1 significantly decreased endogenous Rac1b levels. Although knockdown of AKT2 and AKT3 affected only Rac1b protein levels suggesting a post-splicing effect, the depletion of GSK3ß or SRPK1 decreased Rac1b alternative splicing, an effect mediated through changes in splicing factor SRSF1. In particular, the knockdown of SRPK1 or inhibition of its catalytic activity reduced phosphorylation and subsequent translocation of SRSF1 to the nucleus, limiting its availability to promote the inclusion of alternative exon 3b into the Rac1 pre-mRNA. Altogether, the data identify SRSF1 as a prime regulator of Rac1b expression in colorectal cells and provide further mechanistic insight into how the regulation of alternative splicing events by protein kinases can contribute to sustain tumor cell survival.
Assuntos
Processamento Alternativo/genética , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Nucleares/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas rac1 de Ligação ao GTP/genética , Western Blotting , Núcleo Celular/genética , Neoplasias Colorretais/metabolismo , Éxons/genética , Imunofluorescência , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Microscopia de Fluorescência , Proteínas Nucleares/genética , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Proteínas de Ligação a RNA/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Processamento de Serina-Arginina , Transdução de Sinais , Células Tumorais Cultivadas , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
BACKGROUND: We have previously reported a continuous activation of caspase-1 and increased interleukin (IL)-1ß levels in early rheumatoid arthritis (RA). These observations raised the hypothesis that drugs targeting the IL-1ß pathway, in addition to tumour necrosis factor (TNF), may be particularly effective for early RA treatment. We have recently identified gambogic acid as a promising therapeutic candidate to simultaneously block IL-1ß and TNF secretion. Our main goal here was to investigate whether gambogic acid administration was able to attenuate inflammation in antigen-induced arthritis (AIA) rats. METHODS: Gambogic acid was administered to AIA rats in the early and late phases of arthritis. The inflammatory score, ankle perimeter, and body weight were evaluated during the period of treatment. Rats were sacrificed after 19 days of disease progression and paw samples were collected for histological and immunohistochemical evaluation. RESULTS: We found that inflammation in joints was significantly suppressed following gambogic acid administration. Histological and immunohistochemical evaluation of treated rats revealed normal joint structures with complete abrogation of the inflammatory infiltrate and cellular proliferation. CONCLUSIONS: Our results suggest that gambogic acid has significant anti-inflammatory properties and can possibly constitute a prototype anti-inflammatory drug with therapeutic efficacy in the treatment of inflammatory diseases such as RA.
Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Xantonas/uso terapêutico , Animais , Anti-Inflamatórios/química , Antígenos/química , Artrite Experimental/patologia , Caspase 1/metabolismo , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Feminino , Inflamação , Interleucina-1beta/metabolismo , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVES: Postoperative organ dysfunction is common after cardiac surgery, particularly when cardiopulmonary bypass (CPB) is used. The Sequential Organ Failure Assessment (SOFA) score is validated to predict morbidity and mortality in cardiac surgery. However, the impact of CPB duration on postoperative SOFA remains unclear. METHODS: This is a retrospective study. Categorical values are presented as percentages. The comparison of SOFA groups utilized the Kruskal-Wallis chi-squared test, complemented by ad hoc Dunn's test with Bonferroni correction. Multinomial logistics regressions were employed to evaluate the relationship between CPB time and SOFA. RESULTS: A total of 1032 patients were included. CPB time was independently associated with higher postoperative SOFA scores at 24 h. CPB time was significantly higher in patients with SOFA 4-5 (**P = 0.0022) or higher (***P < 0.001) when compared to SOFA 0-1. The percentage of patients with no/mild dysfunction decreased with longer periods of CPB, down to 0% for CPB time >180min (50% of the patients with >180m in of CPB presented SOFA ≥ 10). The same trend is observed for each of the SOFA variables, with higher impact in the cardiovascular and renal systems. Severe dysfunction occurs especially >200 min of CPB (cardiovascular system >100 min; other systems mainly >200 min). CONCLUSIONS: CPB time may predict the probability of postoperative SOFA categories. Patients with extended CPB durations exhibited higher SOFA scores (overall and for each variable) at 24 h, with higher proportion of moderate and severe dysfunction with increasing times of CPB.
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Sepsis is a leading cause of death in Intensive Care Units. Despite its prevalence, sepsis remains insufficiently understood, with no substantial qualitative improvements in its treatment in the past decades. Immunomodulatory agents may hold promise, given the significance of TNF-α and IL-1ß as sepsis mediators. This study examines the immunomodulatory effects of moxifloxacin, a fluoroquinolone utilized in clinical practice. THP1 cells were treated in vitro with either PBS or moxifloxacin and subsequently challenged with lipopolysaccharide (LPS) or E. coli. C57BL/6 mice received intraperitoneal injections of LPS or underwent cecal ligation and puncture (CLP), followed by treatment with PBS, moxifloxacin, meropenem or epirubicin. Atm-/- mice underwent CLP and were treated with either PBS or moxifloxacin. Cytokine and organ lesion markers were quantified via ELISA, colony-forming units were assessed from mouse blood samples, and DNA damage was evaluated using a comet assay. Moxifloxacin inhibits the secretion of TNF-α and IL-1ß in THP1 cells stimulated with LPS or E. coli. Intraperitoneal administration of moxifloxacin significantly increased the survival rate of mice with severe sepsis by 80% (p < 0.001), significantly reducing the plasma levels of cytokines and organ lesion markers. Notably, moxifloxacin exhibited no DNA damage in the comet assay, and Atm-/- mice were similarly protected following CLP, boasting an overall survival rate of 60% compared to their PBS-treated counterparts (p = 0.003). Moxifloxacin is an immunomodulatory agent, reducing TNF-α and IL-1ß levels in immune cells stimulated with LPS and E. coli. Furthermore, moxifloxacin is also protective in an animal model of sepsis, leading to a significant reduction in cytokines and organ lesion markers. These effects appear unrelated to its antimicrobial activity or induction of DNA damage.
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On the path to successful immunotherapy of hematopoietic tumors, gammadelta T cells offer great promise because of their human leukocyte antigen (HLA)-unrestricted targeting of a wide variety of leukemias/lymphomas. However, the molecular mechanisms underlying lymphoma recognition by gammadelta T cells remain unclear. Here we show that the expression levels of UL16-binding protein 1 (ULBP1) determine lymphoma susceptibility to gammadelta T cell-mediated cytolysis. Consistent with this, blockade of NKG2D, the receptor for ULBP1 expressed on all Vgamma9(+) T cells, significantly inhibits lymphoma cell killing. Specific loss-of-function studies demonstrate that the role of ULBP1 is nonredundant, highlighting a thus far unique physiologic relevance for tumor recognition by gammadelta T cells. Importantly, we observed a very wide spectrum of ULBP1 expression levels in primary biopsies obtained from lymphoma and leukemia patients. We suggest this will impact on the responsiveness to gammadelta T cell-based immunotherapy, and therefore propose ULBP1 to be used as a leukemia/lymphoma biomarker in upcoming clinical trials.
Assuntos
Biomarcadores Tumorais/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Linfócitos T Citotóxicos/metabolismo , Biomarcadores Tumorais/imunologia , Biópsia , Linhagem Celular Tumoral , Ensaios Clínicos como Assunto/métodos , Proteínas Ligadas por GPI , Humanos , Imunoterapia/métodos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Leucemia de Células B/metabolismo , Leucemia de Células B/patologia , Leucemia de Células B/terapia , Leucemia de Células T/metabolismo , Leucemia de Células T/patologia , Leucemia de Células T/terapia , Linfoma/metabolismo , Linfoma/patologia , Linfoma/terapia , Proteínas de Membrana/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , RNA Interferente Pequeno , Linfócitos T Citotóxicos/imunologiaRESUMO
Anthracyclines are among the most used and effective anticancer drugs. Their activity has been attributed to DNA double-strand breaks resulting from topoisomerase II poisoning and to eviction of histones from select sites in the genome. Here, we show that the extensively used anthracyclines Doxorubicin, Daunorubicin, and Epirubicin decrease the transcription of nuclear factor kappa B (NF-κB)-dependent gene targets, but not interferon-responsive genes in primary mouse (Mus musculus) macrophages. Using an NMR-based structural approach, we demonstrate that anthracyclines disturb the complexes formed between the NF-κB subunit RelA and its DNA-binding sites. The anthracycline variants Aclarubicin, Doxorubicinone, and the newly developed Dimethyl-doxorubicin, which share anticancer properties with the other anthracyclines but do not induce DNA damage, also suppressed inflammation, thus uncoupling DNA damage from the effects on inflammation. These findings have implications for anticancer therapy and for the development of novel anti-inflammatory drugs with limited side effects for life-threatening conditions such as sepsis.
Assuntos
Antraciclinas , NF-kappa B , Animais , Camundongos , Antraciclinas/farmacologia , Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Dano ao DNA , DNARESUMO
The 'Crosstalks of immunity and metabolism' Symposium was focused on how the intercommunication between different organs and the immune system affects organismal health. At this meeting, experts in immunology and metabolic research provided novel insights into the growing field of immunometabolism. This report attempts to review and integrate views, ideas, propositions, and conclusions that emanated from the symposium.
Assuntos
Metabolismo Energético/imunologia , Sistema Imunitário/imunologia , Imunidade Inata/imunologia , Inflamação/imunologia , Animais , HumanosRESUMO
OBJECTIVE: Obesity is the result of positive energy balance. It can be caused by excessive energy consumption but also by decreased energy dissipation, which occurs under several conditions including when the development or activation of brown adipose tissue (BAT) is impaired. Here we evaluated whether iRhom2, the essential cofactor for the Tumour Necrosis Factor (TNF) sheddase ADAM17/TACE, plays a role in the pathophysiology of metabolic syndrome. METHODS: We challenged WT versus iRhom2 KO mice to positive energy balance by chronic exposure to a high fat diet and then compared their metabolic phenotypes. We also carried out ex vivo assays with primary and immortalized mouse brown adipocytes to establish the autonomy of the effect of loss of iRhom2 on thermogenesis and respiration. RESULTS: Deletion of iRhom2 protected mice from weight gain, dyslipidemia, adipose tissue inflammation, and hepatic steatosis and improved insulin sensitivity when challenged by a high fat diet. Crucially, the loss of iRhom2 promotes thermogenesis via BAT activation and beige adipocyte recruitment, enabling iRhom2 KO mice to dissipate excess energy more efficiently than WT animals. This effect on enhanced thermogenesis is cell-autonomous in brown adipocytes as iRhom2 KOs exhibit elevated UCP1 levels and increased mitochondrial proton leak. CONCLUSION: Our data suggest that iRhom2 is a negative regulator of thermogenesis and plays a role in the control of adipose tissue homeostasis during metabolic disease.
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Proteínas de Transporte/metabolismo , Obesidade/metabolismo , Termogênese , Animais , Dieta Hiperlipídica/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/induzido quimicamenteRESUMO
The accurate replication and repair of DNA is central to organismal survival. This process is challenged by the many factors that can change genetic information such as replication errors and direct damage to the DNA molecule by chemical and physical agents. DNA damage can also result from microorganism invasion as an integral step of their life cycle or as collateral damage from host defense mechanisms against pathogens. Here we review the complex crosstalk of DNA damage response and immune response pathways that might be evolutionarily connected and argue that DNA damage response pathways can be explored therapeutically to induce disease tolerance through the activation of tissue damage control processes. Such approach may constitute the missing pillar in the treatment of critical illnesses caused by multiple organ failure, such as sepsis and septic shock.
Assuntos
Dano ao DNA/genética , Inflamação/imunologia , Sepse/genética , Choque Séptico/genética , Reparo do DNA/genética , Replicação do DNA/genética , Humanos , Tolerância Imunológica/genética , Inflamação/genética , Inflamação/patologia , Insuficiência de Múltiplos Órgãos/genética , Insuficiência de Múltiplos Órgãos/imunologia , Insuficiência de Múltiplos Órgãos/patologia , Sepse/imunologia , Sepse/patologia , Choque Séptico/imunologia , Choque Séptico/patologia , Transdução de SinaisRESUMO
PURPOSE: Metabolic syndrome and cardiovascular disease are strongly associated with obstructive sleep apnea syndrome (OSAS), which causes substantial changes to normal circadian physiological functions, including metabolic pathways. Because core clock genes are known to be modulated by sleep/vigilance cycles, we asked whether the expression level of mRNA coding for clock genes is altered in non-treated OSAS patients and if it can be corrected by standard continuous positive airway pressure (CPAP) treatment. METHODS: Peripheral blood was collected from male patients diagnosed with severe OSAS (apnea-hypopnea index ≥ 30/h) before and after treatment initiation. qPCR was used to measure mRNA levels of genes associated with the central circadian pacemaker including CLOCK, BMAL1, Cry1, Cry2, and three Period genes (Per 1, 2, 3) in peripheral blood mononuclear cells (PBMCs). RESULTS: We found statistically significant differences for CLOCK (p-value = 0.022) expression in PBMCs of OSAS patients which were not reverted by treatment with CPAP. We have also found a substantial decrease in the slow wave sleep (SWS) content in OSAS patients (p-value < 0.001) that, contrary to REM sleep, was not corrected by CPAP (p-value = 0.875). CONCLUSION: CPAP treatment does not correct substantial changes in expression of core clock genes in OSAS patients. Because CPAP treatment is also unable to normalize the SWS in these patients, it is likely that additional therapeutic interventions that increase SWS content and complement the benefits of CPAP are required to more effectively reduce the known increased cardiovascular risk associated with OSAS patients.
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TET1 is a member of the recently identified family of epigenetic regulators, TET1-3 which catalyze the enzymatic conversion of the methyl mark on cytosine (methylcytosine, mC) to the hydroxymethyl mark (hmC). The functions of hmC are required for stem cell maintenance and for controlling differentiation and reprogramming. So far, no roles for TET proteins have been identified in cells of the immune system. Here we show that TET1 is a negative regulator of IL-1ß transcription following an inflammatory stimulus and negatively modulates IL-1ß secretion in THP-1 cells. In addition, TET1 expression is regulated during inflammation both in THP-1 and in primary dendritic cells. Importantly, other highly induced pro-inflammatory genes are also regulated by TET1, including cytokines, chemokines and adhesion molecules. The other member of the TET family with known roles in stem cell regulation, TET2, is also regulated in THP-1 cells following the inflammatory stimulus and may also participate in IL-1ß regulation, according to our observations. Our results suggest a TET1-dependent anti-inflammatory pathway, which may include TET2. In particular, IL-1ß transcriptional regulation is likely to depend on TET1-regulated chromatin domains. This work highlights the contribution of epigenetic mechanisms to the efficient organization of inflammatory responses.