Diabetes exacerbated sepsis-induced intestinal injury by promoting M1 Macrophage Polarization via miR-3061/Snail1 signaling.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE202261 | GEO | 2022/09/07
REPOSITORIES: GEO
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Project description:BackgroundMacrophages play important roles in diabetes and sepsis-related intestinal injury. Accumulating evidence suggests that microRNAs (miRNAs) act as the fundamental link between macrophage polarization and tissue injury. However, the underlying mechanisms of miRNAs in regulating macrophage polarization-related intestinal injury under diabetes and sepsis conditions remain unclear.MethodsThe cecal ligation and puncture (CLP)-induced sepsis models were established in male wild-type (WT) and diabetic mice. Clodronate liposome was used to deplete macrophage. H&E staining, inflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6], and intestinal mucosal barrier function markers [occludin, ZO-1, lipopolysaccharide (LPS), and intestinal fatty acid binding protein (iFABP)] were used to assess elevated intestinal damage. miRNA array, RNA-seq, and bioinformatic analysis were performed to detect the miRNA and messenger RNA (mRNA) expression and the potential regulation mechanism. In vitro, RAW264.7 cells were cultured in the absence or presence of high glucose and LPS, miR-3061 mimics, and Snail small interfering RNA stimulation, respectively, for further mechanism studies. Luciferase reporter assay was used to confirm the interplay between miRNA and its target genes.ResultsCompared with WT CLP mice, the diabetic CLP mice showed severe intestinal damage characterized by significant increases in Chui's scores, expression of inflammatory cytokines (TNF-α, IL-1β, and IL-6), serum LPS and iFABP concentration, and significant reductions in tight junction protein occludin and ZO-1 levels. Macrophage depletion reversed the intestinal damage caused by CLP. The bioinformatic analysis revealed that miR-3061/Snail1 might be a potential regulation axis of macrophage polarization. Furthermore, high glucose and LPS stimulation increased M1 macrophage and reduced the levels of miR-3061, which was negatively associated with Snail1 in RAW264.7 cells. Mechanistic studies demonstrated that miR-3061 regulated macrophage polarization by targeting the Snail1 mRNA 3'-untranslated region. Moreover, miR-3061 overexpression suppressed Snail1 expression and inhibited M1 macrophage and inflammatory cytokines.ConclusionThis study elucidated that diabetes exacerbated sepsis-induced intestinal injury by promoting M1 macrophage polarization and further demonstrated that the miR-3061/Sani1 axis may be the potential target of macrophage polarization.
| S-EPMC9503829 | biostudies-literature
Project description:Diabetes exacerbated sepsis-induced intestinal injury by promoting M1 Macrophage Polarization via miR-3061/Snail1 signaling.
| PRJNA835149 | ENA
Project description:Sepsis is a severe clinical syndrome related to an exaggerated host immune response to infection as well as systematic inflammation and serious tissue damage. Sepsis-associated acute kidney injury (SA-AKI) is one of the most frequent and serious complications of sepsis. This study aimed to identify new mechanisms in SA-AKI through transcriptome profiling (RNA-seq).
2022-08-17 | GSE186822 | GEO
Project description:Sepsis, a worldwide health crisis, is notorious for its high mortality rate, often attributed to the development of acute lung injury. In this context, the lung, being particularly vulnerable to septic damage, emerge as a primary battleground. The possible roles of the gut-lung axis mediated by the gut microbiota and its metabolic products in the context of acute lung injury have been documented. However, the direct migration of intestinal immune cells to the lung as a mediator of acute lung injury remains unclear. Our study unveiled a process where cecal ligation and puncture-induced sepsis prompted a migration of γδ T cells from the small intestine to the lung, subsequently triggering an overwhelming inflammatory response dominated by IL-17A. Small intestinal memory γδT17 cells (CD44+ IL-7Rhigh CD8low Ly6C–) were the major subtype of γδ T cells that migrated from the small intestine to the lung and aggravated acute lung injury. Moreover, the activation of the Wnt signaling in the alveolar macrophages during sepsis was identified as a driving factor for the subsequent CCL1 upregulation, which prompted the migration of small intestinal memory γδT17 cells to the lung. S-Ketamine (S-KT) treatment demonstrated a notable capacity to alleviate acute lung injury through dampening pulmonary Wnt/β-catenin signaling-mediated migration of small intestinal γδT17 cells to the lung. Our findings highlight the significant contribution of the direct migration of immune cells from the small intestine to the lung in sepsis-induced acute lung injury, and clrify the pathological significance of the localized elevation of IL-17A in the lung.
2024-04-24 | PXD051763 |
Project description:Sepsis, a worldwide health crisis, is notorious for its high mortality rate, often attributed to the development of acute lung injury. The direct migration of intestinal immune cells to the lung as a mediator of acute lung injury remains unclear. Our study unveiled a process where cecal ligation and puncture-induced sepsis prompted a migration of γδT cells from the small intestine to the lung, subsequently triggering an overwhelming inflammatory response dominated by IL-17A.
2024-06-14 | GSE266493 | GEO
Project description:Sepsis, a worldwide health crisis, is notorious for its high mortality rate, often attributed to the development of acute lung injury. The direct migration of intestinal immune cells to the lung as a mediator of acute lung injury remains unclear. Our study unveiled a process where cecal ligation and puncture-induced sepsis prompted a migration of γδT cells from the small intestine to the lung, subsequently triggering an overwhelming inflammatory response dominated by IL-17A.
2024-06-14 | GSE266492 | GEO
Project description:Sepsis is the most common cause of hospitalization worldwide. Millions of people survive sepsis each year and are at risk for rehospitalization and death. Pulmonary complications such as respiratory failure due to pneumonia and exacerbation of chronic respiratory disease are among the most common reasons for rehospitalization in sepsis survivors. In order to prevent additional morbidity and death in patients surviving sepsis, we must establish biomarkers to identify patients at risk for pulmonary complications and develop treatments. Late complications in sepsis survivors, particularly nosocomial infections, are proposed to occur through persistent immune reprogramming after sepsis known as immunoparalysis. However, pro-inflammatory immune reprogramming in the form of primed or enhanced responses to secondary stimuli has also been described and could directly contribute to tissue injury and death. Primed immune responses and their contribution to long-term sepsis complications remains understudied. We hypothesize that primed immune responses to inflammatory stimuli in the lung after sepsis are associated with pulmonary complications in survivors of sepsis. To this end, we developed a model of antibiotic treated sepsis induced by cecal ligation and puncture followed three weeks later by secondary challenge with intranasal lipopolysaccharide to induce inflammatory lung injury. We find that mice surviving sepsis have enhanced lung injury responses in the setting of an exaggerated proinflammatory immune response, including primed Ly6Chi monocyte Tnf expression. Using RNA sequencing, we identified derangements in lung gene expression after CLP prior to LPS administration which may mediate enhanced lung injury in this model. One potential mediator, S100A8/A9, was also found to be elevated in the circulation of human sepsis survivors for up to 180 days after sepsis. These findings validate our model and identify S100A8/A9 as one of many potential biomarkers and therapeutic targets for patients at risk for long-term pulmonary complications after sepsis. The role of S100A8/A9, monocyte priming, and other factors predisposing to enhanced lung injury responses and pulmonary complications after sepsis warrant further investigation in humans and mice.
2021-06-23 | GSE168796 | GEO
Project description:Escherichia coli and Staphylococcus are among the most common causes of bacterial sepsis, a deadly syndrome characterized by uncontrolled activation of coagulation and complement enzymatic cascades an exaggerated immune response. We performed in vivo experimental sepsis in baboons to characterize the host response to bacterial infection in blood cells. We demonstrate that bacterial infection leads to early induction of proinflammatory genes followed by a delayed activation of anti-inflammatory pathways. In addition, we observe changes in genes and pathways associated coagulation and complement as well as with leukocyte adhesion, migration and cell death. Our study provides important insights into the temporal kinetics of gene expression in leukocytes during bacterial sepsis.
2023-06-12 | GSE221652 | GEO
Project description:Acute respiratory distress syndrome (ARDS) is independently associated with a poor prognosis in patients with sepsis. Macrophage M1 polarization plays an instrumental role in this process. Therefore, the exploration of key molecules affecting acute lung injury and macrophage M1 polarization may provide therapeutic targets for the treatment of septic ARDS. Here, we identified that elevated levels of Ankyrin repeat domain-containing protein 22 (ANKRD22) were associated with poor prognosis and more pronounced M1 macrophage polarization in septic patients by analyzing high-throughput data. ANKRD22 expression was also significantly upregulated in the alveolar lavage fluid, peripheral blood, and lung tissue of septic ARDS model mice. Knockdown of ANKRD22 significantly attenuated acute lung injury in mice with sepsis-induced ARDS and reduced the M1 polarization of lung macrophages. Furthermore, deletion of ANKRD22 in macrophages inhibited M1 macrophage polarization and reduced levels of phosphorylated IRF3 and intracellular interferon regulatory factor 3 (IRF3) expression, while re-expression of ANKRD22 reversed these changes. Further experiments revealed that ANKRD22 promotes IRF3 activation by binding to mitochondrial antiviral-signaling protein (MAVS). In conclusion, these findings suggest that ANKRD22 promotes the M1 polarization of lung macrophages and exacerbates sepsis-induced ARDS.
| S-EPMC10788270 | biostudies-literature
Project description:The activation of pulmonary endothelial cells (ECs) triggers the occurrence of lung injury and is a hallmark of sepsis-associated acute respiratory distress syndrome(ARDS). Aberrant metabolism favoring glycolysis plays a pivotal role in the pathogenesis of sepsis-induced EC activation. Herein we demonstrate that glycolysis-related histone lactylation, represented by H3K14 lactylation (H3K14la), drives sepsis-associated EC activation and lung injury. Accordingly, H3K14la level is elevated in injured lung tissue and activated ECs. Inhibition of lactate production suppresses both H3K14la levels and EC activation in response to lipopolysaccharide (LPS). We also show that lactate-dependent H3K14la is enriched at the promoters of ferroptosis-related genes, thereby inducing ferroptosis in ECs, and inhibiting ferroptosis effectively ameliorates EC activation. Taken together, elevated lactate in sepsis modulates EC activation and lung injury via histone lactylation and manipulation of glycolysis/H3K14la/ferroptosis axis may provide novel therapeutic approaches for the treatment of sepsis-associated ARDS.
2023-01-01 | GSE212087 | GEO