Morphine induced exacerbation of sepsis is mediated by tempering endotoxin tolerance through modulation of miR-146a.
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ABSTRACT:
SUBMITTER: Banerjee S
PROVIDER: S-EPMC3679508 | biostudies-literature | 2013
REPOSITORIES: biostudies-literature
Publications
Morphine induced exacerbation of sepsis is mediated by tempering endotoxin tolerance through modulation of miR-146a.
Banerjee Santanu S Meng Jingjing J Das Subhas S Krishnan Anitha A Haworth Justin J Charboneau Richard R Zeng Yan Y Ramakrishnan Sundaram S Roy Sabita S
Scientific reports 20130101
Development of tolerance to endotoxin prevents sustained hyper inflammation during systemic infections. Here we report for the first time that chronic morphine treatment tempers endotoxin tolerance resulting in persistent inflammation, septicemia and septic shock. Morphine was found to down-regulate endotoxin/LPS induced miR-146a and 155 in macrophages. However, only miR-146a over expression, but not miR-155 abrogates morphine mediated hyper-inflammation. Conversely, antagonizing miR-146a (but n ...[more]
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Project description:Endotoxin/LPS tolerance is a tightly regulated phenomenon, which, during infection, prevents systemic hyper-inflammation. Here we report for the first time that morphine reversal of endotoxin tolerance resulting in persistent inflammation thus contributing to septicemia and septic shock. We further report that this regulation is mediated by LPS-induced down-regulation of microRNAs 146a and 155. However, only over-expression of miR-146a, but not miR-155 abrogates morphine mediated hyper-inflammation, while antagonizing miR-146a (but not miR-155) augments morphine mediated hyper-inflammation. Hence, miR-146a could be the potential therapeutic target for morphine-mediated abrogation of endotoxin tolerance. All treatments done in vivo. Morphine implanted subcuteniously, LPS administered as intraperitoneal injection.
2013-08-01 | E-GEOD-42506 | biostudies-arrayexpress
Project description:Endotoxin/LPS tolerance is a tightly regulated phenomenon, which, during infection, prevents systemic hyper-inflammation. Here we report for the first time that morphine reversal of endotoxin tolerance resulting in persistent inflammation thus contributing to septicemia and septic shock. We further report that this regulation is mediated by LPS-induced down-regulation of microRNAs 146a and 155. However, only over-expression of miR-146a, but not miR-155 abrogates morphine mediated hyper-inflammation, while antagonizing miR-146a (but not miR-155) augments morphine mediated hyper-inflammation. Hence, miR-146a could be the potential therapeutic target for morphine-mediated abrogation of endotoxin tolerance.
2013-08-01 | GSE42506 | GEO
Project description:Endotoxin tolerance is a phenomenon characterized by a reduced capacity of monocytes and macrophages to respond to repeated stimulation with lipopolysaccharide (LPS) which has been suggested to represent a way of controlling the intensity and duration of innate immune response. During endotoxin tolerance, monocytes undergo functional re-programming primarily by epigenetic regulation. Recently, micro-RNA (miR)-146a has been demonstrated to be the major player of the negative regulation of the pro-inflammatory response, affecting TNF-α production. In this study, we have employed CyP, a cyanobacterial LPS antagonist acting on TLR4-MD2 complex, for priming human monocytes and evaluating their response to a subsequent challenge with E. coli LPS. Results show that CyP is able to induce cross-tolerance to E. coli LPS by inhibiting TNF-α production. The mechanism of action is mediated by a specific induction of miR-146a and reduction of IRAK1 and TRAF6 expressions in human monocytes by CyP priming. Up-regulation of miR-146a by CyP alone, affects subsequent cell response in term of TNF-α production even when monocytes are incubated with other TLR ligands, as lipoteichoic acid (LTA), thus confirming miR-146a as a critical player mediating TNF-α regulation during cross-tolerance with CyP.
| S-EPMC6063882 | biostudies-literature
Project description:Innate immune response is the first defense against pathogens via recognition by various conserved pattern recognition receptors, such as TLRs, to initiate a rapid and strong cytokine alarm. TLR signaling-mediated cytokine production must be properly regulated to prevent pathological conditions deriving from overproduction of cytokines. In this study, the role of specific microRNAs in TLR-signaling pathway was investigated to reveal the cross-interaction and -regulation in the MyD88 pathway. In peptidoglycan (PGN)/TLR2-stimulated THP-1 monocytes, PBMCs, and primary macrophages showed rapid and dramatic miR-132 and miR-212 (miR-132/-212) upregulation. This newly identified response appeared earlier in time than the characteristic miR-146a response in LPS-TLR4 stimulation. The rapid induction of miR-132/-212 was transcription factor CREB dependent, and the sustained expression of miR-132/-212 was responsible for inducing tolerance to subsequent PGN challenge. Cross-tolerance was observed by TLR5 ligand flagellin and heat-killed or live bacteria resulting from miR-132/-212 upregulation. Mechanistically, IRAK4 was identified and validated as a target of miR-132/-212 by luciferase reporter assay and seed-sequence mutagenesis of the reporter. Transfection of miR-132 or miR-212 alone mimicked PGN tolerance in monocytes, whereas transfected specific miRNA inhibitors tampered the tolerance effect. During bacterial infection, PGN-mediated TLR2 signaling induces miR-132/-212 to downregulate IRAK4, an early component in the MyD88-dependent pathway, whereas LPS/TLR4-induced miR-146a downregulates downstream components of the same MyD88-dependent pathway. The identification of miR-132/-212 and miR-146a together to prevent damaging consequences from the overproduction of proinflammatory cytokines by targeting a common signaling pathway is significant and will provide insights into future design and development of therapeutics.
| S-EPMC3552145 | biostudies-literature
Project description:BackgroundSepsis involves aberrant immune responses to infection, but the exact nature of this immune dysfunction remains poorly defined. Bacterial endotoxins like lipopolysaccharide (LPS) are potent inducers of inflammation, which has been associated with the pathophysiology of sepsis, but repeated exposure can also induce a suppressive effect known as endotoxin tolerance or cellular reprogramming. It has been proposed that endotoxin tolerance might be associated with the immunosuppressive state that was primarily observed during late-stage sepsis. However, this relationship remains poorly characterised. Here we clarify the underlying mechanisms and timing of immune dysfunction in sepsis.MethodsWe defined a gene expression signature characteristic of endotoxin tolerance. Gene-set test approaches were used to correlate this signature with early sepsis, both newly and retrospectively analysing microarrays from 593 patients in 11 cohorts. Then we recruited a unique cohort of possible sepsis patients at first clinical presentation in an independent blinded controlled observational study to determine whether this signature was associated with the development of confirmed sepsis and organ dysfunction.FindingsAll sepsis patients presented an expression profile strongly associated with the endotoxin tolerance signature (p < 0.01; AUC 96.1%). Importantly, this signature further differentiated between suspected sepsis patients who did, or did not, go on to develop confirmed sepsis, and predicted the development of organ dysfunction.InterpretationOur data support an updated model of sepsis pathogenesis in which endotoxin tolerance-mediated immune dysfunction (cellular reprogramming) is present throughout the clinical course of disease and related to disease severity. Thus endotoxin tolerance might offer new insights guiding the development of new therapies and diagnostics for early sepsis.
| S-EPMC4326653 | biostudies-literature
Project description:BackgroundLimited studies have functionally evaluated the heterogeneity in early ex vivo immune responses during sepsis. Our aim was to characterize early sepsis ex vivo functional immune response heterogeneity by studying whole blood endotoxin responses and derive a transcriptional metric of ex vivo endotoxin response.MethodsBlood collected within 24 h of hospital presentation from 40 septic patients was divided into two fractions and incubated with media (unstimulated) or endotoxin. Supernatants and cells were isolated, and responses measured using: supernatant cytokines, lung endothelial permeability after supernatant exposure, and RNA expression. A transcriptomic signature was derived in unstimulated cells to predict the ex vivo endotoxin response. The signature was tested in a separate cohort of 191 septic patients to evaluate for association with clinical outcome. Plasma biomarkers were quantified to measure in vivo host inflammation.ResultsEx vivo response to endotoxin varied and was unrelated to immunosuppression, white blood cell count, or the causative pathogen. Thirty-five percent of patients demonstrated a minimal response to endotoxin, suggesting early immunosuppression. High ex vivo cytokine production by stimulated blood cells correlated with increased in vitro pulmonary endothelial cell permeability and was associated with attenuated in vivo host inflammation. A four-gene signature of endotoxin response detectable without the need for a functional assay was identified. When tested in a separate cohort of septic patients, its expression was inversely associated with hospital mortality.ConclusionsAn attenuated ex vivo endotoxin response in early sepsis is associated with greater host in vivo inflammation and a worse clinical outcome.
| S-EPMC9246838 | biostudies-literature
Project description:Background: Sepsis involves aberrant immune responses to infection, but the exact nature of this immune dysfunction remains poorly defined. Bacterial endotoxins like lipopolysaccharide (LPS) are potent inducers of inflammation, which has been associated with the pathophysiology of sepsis, but repeated exposure can also induce a suppressive effect known as endotoxin tolerance or cellular reprogramming. It has been proposed that endotoxin tolerance might be associated with the immunosuppressive state that was primarily observed during late-stage sepsis. However, this relationship remains poorly characterised. Here we clarify the underlying mechanisms and timing of immune dysfunction in sepsis. Methods: We defined a gene expression signature characteristic of endotoxin tolerance. Gene-set test approaches were used to correlate this signature with early sepsis, both newly and retrospectively analysing microarrays from 593 patients in 11 cohorts. Then we recruited a unique cohort of possible sepsis patients at first clinical presentation in an independent blinded controlled observational study to determine whether this signature was associated with the development of confirmed sepsis and organ dysfunction. Findings: All sepsis patients presented an expression profile strongly associated with the endotoxin tolerance signature (p < 0.01; AUC 96.1%). Importantly, this signature further differentiated between suspected sepsis patients who did, or did not, go on to develop confirmed sepsis, and predicted the development of organ dysfunction. Interpretation: Our data support an updated model of sepsis pathogenesis in which endotoxin tolerance-mediated immune dysfunction (cellular reprogramming) is present throughout the clinical course of disease and related to disease severity. Thus endotoxin tolerance might offer new insights guiding the development of new therapies and diagnostics for early sepsis. For the RNA-Seq study reported here, 73 patients were recruited with deferred consent at the time of first examination in an emergency ward based on the opinion of physicians that there was a potential for the patient's condition to develop into sepsis. These were retrospectively divided into groups based on clinical features and compared to 11 non-urgent surgical controls.
2014-11-14 | E-GEOD-63311 | biostudies-arrayexpress
Project description:Background: Sepsis involves aberrant immune responses to infection, but the exact nature of this immune dysfunction remains poorly defined. Bacterial endotoxins like lipopolysaccharide (LPS) are potent inducers of inflammation, which has been associated with the pathophysiology of sepsis, but repeated exposure can also induce a suppressive effect known as endotoxin tolerance or cellular reprogramming. It has been proposed that endotoxin tolerance might be associated with the immunosuppressive state that was primarily observed during late-stage sepsis. However, this relationship remains poorly characterised. Here we clarify the underlying mechanisms and timing of immune dysfunction in sepsis. Methods: We defined a gene expression signature characteristic of endotoxin tolerance. Gene-set test approaches were used to correlate this signature with early sepsis, both newly and retrospectively analysing microarrays from 593 patients in 11 cohorts. Then we recruited a unique cohort of possible sepsis patients at first clinical presentation in an independent blinded controlled observational study to determine whether this signature was associated with the development of confirmed sepsis and organ dysfunction. Findings: All sepsis patients presented an expression profile strongly associated with the endotoxin tolerance signature (p < 0.01; AUC 96.1%). Importantly, this signature further differentiated between suspected sepsis patients who did, or did not, go on to develop confirmed sepsis, and predicted the development of organ dysfunction. Interpretation: Our data support an updated model of sepsis pathogenesis in which endotoxin tolerance-mediated immune dysfunction (cellular reprogramming) is present throughout the clinical course of disease and related to disease severity. Thus endotoxin tolerance might offer new insights guiding the development of new therapies and diagnostics for early sepsis.
2014-11-14 | GSE63311 | GEO
Project description:Morphine tolerance is a challenging clinical problem that limits its clinical application in pain treatment. Non-coding microRNAs (miRNAs) modulate gene expression in a post transcriptional manner, and their dysregulation causes various diseases. However, the significance of miRNAs in morphine tolerance is still poorly understood. In the present study, we hypothesized that microRNA-365 (miR-365) is a key functional small RNA that reverses morphine tolerance through regulation of β-arrestin 2 in rats. Here, microarray analysis and quantitative real-time PCR showed that miR-365 was robustly decreased in the spinal cord after chronic morphine administration. In situ hybridization and immunochemistry double staining showed that miR-365 was expressed in neurons of the spinal cord. We identified β-arrestin 2 as the target gene of miR-365 by bioinformatics analysis and luciferase reporter assay. The data showed that overexpression of miR-365 prevented and reversed established morphine tolerance, and increased expression of miR-365 caused a decrease in expression of β-arrestin 2 protein. miR-365 downregulation is involved in the development and maintenance of morphine tolerance through regulation of β-arrestin 2, and miR-365 upregulation provides a promising and novel approach for treatment of morphine tolerance.
| S-EPMC5138852 | biostudies-literature
Project description:BackgroundEndotoxin tolerance (ET) is a protective mechanism in the process of sepsis, septic shock, and their sequelae including uncontrolled inflammation. Accumulating evidence has shown that peripheral T cells contribute to the induction of ET. However, what and how T-cell development contributes to ET inductions remain unclear.MethodsMice were intraperitoneally injected with LPS at a concentration of 5 mg/kg to establish an LPS tolerance model and were divided into two groups: a group examined 72 h after LPS injection (72-h group) and a group examined 8 days after LPS injection (8-day group). Injection of PBS was used as a control. We performed high-throughput sequencing to analyze the characteristics and changes of CD4+SP TCRβ CDR3 repertoires with respect to V direct to J rearrangement during the ET induction. Moreover, the proportion and proliferation, as well as surface molecules such as CD80 and CD86, of F4/80+ macrophages were analyzed using FCM. Furthermore, ACT assay was designed and administered by the tail vein into murine LPS-induced mouse model to evaluate the role of F4/80+ macrophages on the development of CD4+SP thymocytes in ET condition.ResultsWe found that the frequency and characteristics of the TCRβ chain CDR3 changed obviously under condition of ET, indicating the occurrence of TCR rearrangement and thymocyte diversification. Moreover, the absolute numbers of F4/80+ macrophages, but not other APCs, were increased in thymic medulla at 72-h group, accompanied by the elevated function-related molecules of F4/80+ macrophages. Furthermore, adoptively transferred OVA332-339 peptide-loaded macrophages into Rag-1-/- mice induced the clone deletion of OVA-specific CD4+SP, thereby ameliorating the pathology in lung tissue in LPS challenge.ConclusionsThese data reveal that the frequency and characteristics of the TCRβ chain CDR3 undergo dynamic programming under conditions of LPS tolerance. Furthermore, the peripheral macrophages may be a key factor which carry peripheral antigen to thymic medulla and affect the negative selection of T-cell population, thereby contributing to the formation of ET. These results suggest that the clone selection in thymus in ET may confer protection against microbial sepsis.
| S-EPMC10023648 | biostudies-literature