RORγt+IL-17+ neutrophils play a critical role in hepatic ischemia-reperfusion injury.
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ABSTRACT:
SUBMITTER: Tan Z
PROVIDER: S-EPMC3934999 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Neutrophils play critical roles during the initial phase of hepatic ischemia/reperfusion injury (HIRI). However, the regulation of neutrophil activation, infiltration, and proinflammatory cytokine secretion has not been fully elucidated. In this study, we revealed that OX40 was expressed by neutrophils, its expression in neutrophils was time-dependently upregulated following HIRI, and Ox40 knockout markedly alleviated liver injury. Compared with wild-type neutrophils, the adoptive transfer of Ox40-/- neutrophils decreased HIRI in neutrophil-depleted Rag2/Il2rg-/- or Ox40-/- mice. Moreover, consistently, the in vitro experiments showed that Ox40 not only prolonged neutrophil survival but also promoted proinflammatory cytokines, ROS production, and even neutrophil chemotaxis. Further investigation demonstrated that the knockout of Ox40 in neutrophils inhibited NF-?B signaling via the TRAF1/2/4 and IKK?/IKK?/I?B? pathways. OX40L and OX86 stimulation could enhance neutrophil activation and survival in vitro and in vivo. In conclusion, our study provides a new understanding of OX40, which is expressed not only in adaptive immune cells but also in innate immune cells, i.e., neutrophils, contributing to the activation and survival of neutrophils. These findings provide a novel potential therapeutic target for the prevention of HIRI during liver transplantation or hepatic surgery.
| S-EPMC6948758 | biostudies-literature
Project description:The IL-23/IL-17 and IL-12/IFN-gamma cytokine pathways have a role in chronic autoimmunity, which is considered mainly a dysfunction of adaptive immunity. The extent to which they contribute to innate immunity is, however, unknown. We used a mouse model of acute kidney ischemia-reperfusion injury (IRI) to test the hypothesis that early production of IL-23 and IL-12 following IRI activates downstream IL-17 and IFN-gamma signaling pathways and promotes kidney inflammation. Deficiency in IL-23, IL-17A, or IL-17 receptor (IL-17R) and mAb neutralization of CXCR2, the p19 subunit of IL-23, or IL-17A attenuated neutrophil infiltration in acute kidney IRI in mice. We further demonstrate that IL-17A produced by GR-1+ neutrophils was critical for kidney IRI in mice. Activation of the IL-12/IFN-gamma pathway and NKT cells by administering alpha-galactosylceramide-primed bone marrow-derived DCs increased IFN-gamma production following moderate IRI in WT mice but did not exacerbate injury or enhance IFN-gamma production in either Il17a-/- or Il17r-/- mice, which suggested that IL-17 signaling was proximal to IFN-gamma signaling. This was confirmed by the finding that IFN-gamma administration reversed the protection seen in Il17a-/- mice subjected to IRI, whereas IL-17A failed to reverse protection in Ifng-/- mice. These results demonstrate that the innate immune component of kidney IRI requires dual activation of the IL-12/IFN-gamma and IL-23/IL-17 signaling pathways and that neutrophil production of IL-17A is upstream of IL-12/IFN-gamma. These mechanisms might contribute to reperfusion injury in other organs.
| S-EPMC2798679 | biostudies-literature
Project description:RationaleWe recently implicated a role for CD4(+) T cells and demonstrated elevated IL-17A expression in lung ischemia-reperfusion (IR) injury. However, identification of the specific subset of CD4(+) T cells and their mechanistic role in IR injury remains unknown.ObjectivesWe tested the hypothesis that invariant natural killer T (iNKT) cells mediate lung IR injury via IL-17A signaling.MethodsMice underwent lung IR via left hilar ligation. Pulmonary function was measured using an isolated lung system. Lung injury was assessed by measuring edema (wet/dry weight) and vascular permeability (Evans blue dye). Inflammation was assessed by measuring proinflammatory cytokines in lungs, and neutrophil infiltration was measured by immunohistochemistry and myeloperoxidase levels.Measurements and main resultsPulmonary dysfunction (increased airway resistance and pulmonary artery pressure and decreased pulmonary compliance), injury (edema, vascular permeability), and inflammation (elevated IL-17A; IL-6; tumor necrosis factor-?; monocyte chemotactic protein-1; keratinocyte-derived chemokine; regulated upon activation, normal T-cell expressed and secreted; and neutrophil infiltration) after IR were attenuated in IL-17A(-/-) and Rag-1(-/-) mice. Anti-IL-17A antibody attenuated lung dysfunction in wild-type mice after IR. Reconstitution of Rag-1(-/-) mice with wild-type, but not IL-17A(-/-), CD4(+) T cells restored lung dysfunction, injury, and inflammation after IR. Lung dysfunction, injury, IL-17A expression, and neutrophil infiltration were attenuated in J?18(-/-) mice after IR, all of which were restored by reconstitution with wild-type, but not IL-17A(-/-), iNKT cells. Flow cytometry and enzyme-linked immunosorbent spot assay confirmed IL-17A production by iNKT cells after IR.ConclusionsThese results demonstrate that CD4(+) iNKT cells play a pivotal role in initiating lung injury, inflammation, and neutrophil recruitment after IR via an IL-17A-dependent mechanism.
| S-EPMC3137143 | biostudies-literature
Project description:Eosinophils are a myeloid cell subpopulation that mediates type 2 T helper cell immune responses. Unexpectedly, we identified a rapid accumulation of eosinophils in 22 human liver grafts after hepatic transplantation. In contrast, no eosinophils were detectable in healthy liver tissues before transplantation. Studies with two genetic mouse models of eosinophil deficiency and a mouse model of antibody-mediated eosinophil depletion revealed exacerbated liver injury after hepatic ischemia and reperfusion. Adoptive transfer of bone marrow-derived eosinophils normalized liver injury of eosinophil-deficient mice and reduced hepatic ischemia and reperfusion injury in wild-type mice. Mechanistic studies combining genetic and adoptive transfer approaches identified a critical role of suppression of tumorigenicity (ST2)-dependent production of interleukin-13 by eosinophils in the hepatoprotection against ischemia-reperfusion-induced injury. Together, these data provide insight into a mechanism of eosinophil-mediated liver protection that could serve as a therapeutic target to improve outcomes of patients undergoing liver transplantation.
| S-EPMC8167890 | biostudies-literature
Project description:Background:Hepatic ischemia and reperfusion (I/R) is common in liver surgery and transplantation and compromises postoperative liver function. Hepatic I/R injury is characterized by sterile inflammation that contributes to hepatocellular necrosis. Many immune cells and cytokines have been implicated in hepatic I/R injury. However, the role and relevance of IL-23 and IL-17A remains controversial in literature. Aim: To determine whether the IL-23/IL-17A signaling axis is activated in hepatic I/R using a triple-level experimental approach (in vitro, in vivo, and clinical). Methods:IL-23 and IL-17A were assayed by ELISA in the supernatant fractions of cultured murine (RAW 264.7) macrophages that were activated by supernatant fractions of necrotic cultured mouse (AML12) hepatocytes. Similarly, levels of these cytokines were determined in plasma samples and liver tissue of mice (N = 85) subjected to partial (70%) liver I/R. Finally, IL-23 and IL-17A were assayed in plasma samples obtained from a controlled cohort of liver resection patients who were either subjected to I/R (N = 27) or not (N = 13). Results:Activated macrophages did not produce IL-23 in response to supernatant of necrotic AML12 hepatocytes. IL-23 and IL-17A were not elevated in mice subjected hepatic I/R and were not elevated in serum from patients subjected to I/R during liver resection. Conclusion:IL-23 and IL-17A are not involved in hepatic I/R injury in mouse and man. Relevance for patients:If IL-23 and IL-17A were to mediate hepatocellular injury following I/R, these cytokines would constitute potential therapeutic targets. Since this study has revealed that IL-23 and IL-17A do not play a role in hepatic I/R, other pathways and therapeutic targets should be considered when developing modalities aimed at reducing hepatic I/R injury.
| S-EPMC6410619 | biostudies-literature
Project description:Hepatic ischemia-reperfusion injury (IRI) limits access to transplantation. Heme oxygenase-1 (HO-1) is a powerful antioxidant enzyme which degrades free heme into biliverdin, free iron and carbon monoxide. HO-1 and its metabolites have the ability to modulate a wide variety of inflammatory disorders including hepatic IRI. Mechanisms of this protective effect include reduction of oxygen free radicals, alteration of macrophage and T cell phenotype. Further work is required to understand the physiological importance of the many actions of HO-1 identified experimentally, and to harness the protective effect of HO-1 for therapeutic potential.
| S-EPMC3012573 | biostudies-literature
Project description:Hepatic ischemia reperfusion (IR) is the leading cause of acute liver failure (ALF) during the perioperative period and patients with ALF frequently develop acute kidney injury (AKI). There is no effective therapy for AKI associated with ALF because pathomechanisms are incompletely characterized, in part due to the lack of an animal model. In this study, we characterize a novel murine model of AKI following hepatic IR. Mice subjected to approximately 70% liver IR not only developed acute liver dysfunction, but also developed severe AKI 24 h after liver injury. Mice subjected to liver IR developed histological changes of acute tubular injury including focal proximal tubular cell necrosis involving the S3 segment, cortical tubular ectasia, focal tubular simplification and granular bile/heme cast formation. In addition, there was focal interstitial edema and hyperplasia of the juxtaglomerular apparatus. Inflammatory changes in the kidney after hepatic IR included neutrophil infiltration of the interstitium and upregulation of several proinflammatory mRNAs (tumor necrosis factor-alpha, keratinocyte-derived cytokine, monocyte chemotactic protein-1, macrophage inflammatory protein-2, intercellular adhesion molecule-1). In addition, marked renal endothelial cell apoptosis was detected involving peritubular interstitial capillaries, accompanied by increased renal vascular permeability. Finally, there was severe disruption of renal proximal tubule epithelial filamentous-actin. Our results show that AKI rapidly and reproducibly develops in mice after hepatic IR and is characterized by renal tubular necrosis, inflammatory changes and interstitial capillary endothelial apoptosis. Our murine model of AKI after liver injury closely mimics human AKI associated with ALF and may be useful in delineating the mechanisms and potential therapies for this common clinical condition.
| S-EPMC2632727 | biostudies-literature
Project description:BackgroundIL-17A and IL-17F are pro-inflammatory cytokines which induce the expression of several cytokines, chemokines and matrix metalloproteinases (MMPs) in target cells. IL-17 cytokines have recently attracted huge interest due to their pathogenic role in diseases such as arthritis and inflammatory bowel disease although a role for IL-17 cytokines in myocardial infarction (MI) has not previously been described.MethodsIn vivo MI was performed by coronary artery occlusion in the absence or presence of a neutralizing IL-17 antibody for blocking IL-17 actions in vivo. IL-17 signaling was also assessed in isolated primary cardiomyocytes by Western blot, mRNA expression and immunostaining.ResultsExpression of IL-17A, IL-17F and the IL-17 receptor (IL-17RA) were all increased following MI. Expression of several IL-17 target genes, including Cxcl1, Cxcl2, IL-1β, iNOS and IL-6 was also upregulated following MI. In addition, IL-17A promoted the expression of Cxcl1 and IL-6 in isolated cardiomyocytes in a MAPK and PI(3)K-dependent manner. IL-17A and ischaemia/reperfusion (I/R) injury were found to have an additive effect on Cxcl1 expression, suggesting that IL-17 may enhance myocardial neutrophil recruitment during MI. Moreover, protein levels of both IL-17R and IL-17A were enhanced following in vivo MI. Finally, blocking IL-17 signaling in vivo reduced the levels of apoptotic cell death markers following in vivo MI.ConclusionsThese data imply that the expression of IL-17 cytokines and their receptor are elevated during myocardial I/R injury and may play a fundamental role in post infarct inflammatory and apoptotic responses.
| S-EPMC3581775 | biostudies-literature
Project description:Methods: Methods: To better understand the role of resveratrol in the regulation of neutrophils activation and function, neutrophils with or without resveratrol in the expose of LPS were compared in a transcriptome sequencing study. Total RNA was isolated from bone marrow and FACS-separated neutrophils. Transcriptome sequencing libraries were generated using NEBNext® Ultra™ RNA Library Prep Kit for Illumina® (NEB, USA) following manufacturer’s recommendations and sequenced on an Illumina Hiseq platform (Illumina, San Diego, CA). Sequences were aligned to the reference genome with TopHat and processed with Cufflinks, which quantifies each transcript in each sample using reference annotations produced bythe University of California Santa Cruz UCSC. Differentially expressed genes with a fold change of >=2.0 and p value<0.01 between resveratrol treated and control neutrophils were submitted to GO and KEGG enrichment analysis, which uses unbiased methods to assess pathway enrichment. Results: Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that downregulated genes from resveratrol-stimulated neutrophils are involved in neutrophil migration, neutrophil chemotaxis, TNF signaling pathway and cytokine activity, among other. Compared to control neutrophils, neutrophils with resveratrol exhibited downregulated levels of cell survival related genes (Camkk1, Aqp1, Bcl2a1b, etc), cell cycle related genes (Ccnb1, Ccnb2, Cdc20, Cdk1, etc), adhesion and migration related genes (Cass4, Nectin4, Gp5, Gpr35, etc), and cytokines (Csf1, Csf3, Ccl2, Ccl7, Ccl12).
2023-02-09 | GSE215236 | GEO
Project description:We previously developed IM-54 as a novel type of inhibitor of hydrogen-peroxide-induced necrotic cell death. Here, we examined its cell death inhibition profile. IM-54 was found to selectively inhibit oxidative stress-induced necrosis, but it did not inhibit apoptosis induced by various anticancer drugs or Fas ligand, or necroptosis. IM-17, an IM derivative having improved water-solubility and metabolic stability, was developed and confirmed to retain necrosis-inhibitory activity. IM-17 showed cardioprotective effects in an isolated rat heart model and an in vivo arrhythmia model, suggesting that IM derivatives may have therapeutic potential.
| S-EPMC5846036 | biostudies-literature