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Exosome-mediated pyroptosis of miR-93-TXNIP-NLRP3 leads to functional difference between M1 and M2 macrophages in sepsis-induced acute kidney injury.

ABSTRACT: Sepsis is a systemic inflammatory response syndrome caused by infection, resulting in organ dysfunction. Sepsis-induced acute kidney injury (AKI) is one of the most common potential complications. Increasing reports have shown that M1 and M2 macrophages both take part in the progress of AKI by influencing the level of inflammatory factors and the cell death, including pyroptosis. However, whether M1 and M2 macrophages regulate AKI by secreting exosome remains unknown. In the present study, we isolated the exosomes from M1 and M2 macrophages and used Western blot and enzyme-linked immunosorbent assay (ELISA) to investigate the effect of M1 and M2 exosomes on cell pyroptosis. miRNA sequencing was used to identify the different miRNA in M1 and M2 exosomes. Luciferase reporter assay was used to verify the target gene of miRNA. We confirmed that exosomes excreted by macrophages regulated cell pyroptosis in vitro by using Western blot and ELISA. miRNA sequencing revealed the differentially expressed level of miRNAs in M1 and M2 exosomes, among which miR-93-5p was involved in the regulation of pyroptosis. By using bioinformatics predictions and luciferase reporter assay, we found that thioredoxin-interacting protein (TXNIP) was a direct target of miR-93-5p. Further in vitro and in vivo experiments indicated that exosomal miR-93-5p regulated the TXNIP directly to influence the pyroptosis in renal epithelial cells, which explained the functional difference between different phenotypes of macrophages. This study might provide new targets for the treatment of sepsis-induced AKI.

SUBMITTER: Juan CX

PROVIDER: S-EPMC8107088 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Metformin protects against intestinal ischemia-reperfusion injury and cell pyroptosis via TXNIP-NLRP3-GSDMD pathway.

Project description:Intestinal ischemia-reperfusion (I/R) injury is a life-threatening vascular emergency and has long been a disturbing problem for surgeons. Oxidative stress is considered a vital factor in I/R injury. Metformin has anti-oxidative properties and protects against I/R injury. The present study aimed to investigate whether Metformin protects against intestinal I/R injury and reveal the protective mechanism of Metformin. I/R injury was induced in mice by temporary superior mesenteric artery occlusion, and Caco-2 cells were subjected to OGD/R to establish an in vitro model. Different doses of Metformin were administered in vivo and in vitro. We found that I/R injury led to intestinal barrier disruption and cell death by examining histopathological results and the intestinal barrier index, including TER, tight junction proteins and serum biomarkers. We confirmed the existence of pyroptosis in intestinal I/R injury. Moreover, we confirmed the role of pyroptosis in intestinal I/R injury by silencing the gasdermin D (GSDMD). Then, we confirmed that Metformin treatment protected barrier function against intestinal I/R injury and reduced oxidative stress and the inflammatory response. Importantly, Metformin reduced pyroptosis-related proteins, including NLRP3, cleaved caspase-1, and the N-terminus of GSDMD. Knocking down the GSDMD could reversed the protective effects of Metformin, which showed pyroptosis was one of the major cell death pathways controlled by Metformin treatment in setting of intestinal I/R injury. We also discovered that Metformin suppressed the expression of TXNIP and the interaction between TXNIP and NLRP3. We performed siRNA knockdown and found that the protective effects were abolished, which further confirmed our findings. In conclusion, we believe that Metformin protects against intestinal I/R injury in a TXNIP-NLRP3-GSDMD-dependent manner.

| S-EPMC7178548 | biostudies-literature

Exosome-Guided Phenotypic Switch of M1 to M2 Macrophages for Cutaneous Wound Healing.

Project description:Macrophages (Mϕs) critically contribute to wound healing by coordinating inflammatory, proliferative, and angiogenic processes. A proper switch from proinflammatory M1 to anti-inflammatory M2 dominant Mϕs accelerates the wound healing processes leading to favorable wound-care outcomes. Herein, an exosome-guided cell reprogramming technique is proposed to directly convert M1 to M2 Mϕs for effective wound management. The M2 Mϕ-derived exosomes (M2-Exo) induce a complete conversion of M1 to M2 Mϕs in vitro. The reprogrammed M2 Mϕs turn Arginase (M2-marker) and iNOS (M1-marker) on and off, respectively, and exhibit distinct phenotypic and functional features of M2 Mϕs. M2-Exo has not only Mϕ reprogramming factors but also various cytokines and growth factors promoting wound repair. After subcutaneous administration of M2-Exo into the wound edge, the local populations of M1 and M2 Mϕs are markedly decreased and increased, respectively, showing a successful exosome-guided switch to M2 Mϕ polarization. The direct conversion of M1 to M2 Mϕs at the wound site accelerates wound healing by enhancing angiogenesis, re-epithelialization, and collagen deposition. The Mϕ phenotype switching induced by exosomes possessing the excellent cell reprogramming capability and innate biocompatibility can be a promising therapeutic approach for various inflammation-associated disorders by regulating the balance between pro- versus anti-inflammatory Mϕs.

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Taurine Alleviates Schistosoma-Induced Liver Injury by Inhibiting the TXNIP/NLRP3 Inflammasome Signal Pathway and Pyroptosis.

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| S-EPMC6867867 | biostudies-literature

Inhibition of the PERK/TXNIP/NLRP3 Axis by Baicalin Reduces NLRP3 Inflammasome-Mediated Pyroptosis in Macrophages Infected with <i>Mycobacterium tuberculosis</i>.

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| S-EPMC8592748 | biostudies-literature

MiR-17-5p Inhibits TXNIP/NLRP3 Inflammasome Pathway and Suppresses Pancreatic β-Cell Pyroptosis in Diabetic Mice.

Project description:Objective: Diabetes mellitus is a chronic progressive inflammatory metabolic disease with pancreatic β-cells dysfunction. The present study aimed to investigate whether miR-17-5p plays a protective effect on pancreatic β-cells function in diabetes mellitus (DM) mice and dissect the underlying mechanism. Methods: C57BL/6J mice were randomly divided into control, DM, DM + Lentivirus negative control (LV-NC), and DM + Lenti-OE™ miR-17-5p (LV-miR-17-5) groups. DM was established by feeding a high-fat diet and intraperitoneal injection with streptozotocin (STZ) in mice. Blood glucose and glucose tolerance in circulation were measured. Meanwhile, the activation of nod-like receptor protein 3 (NLRP3) inflammasome, pancreas pyroptosis, and the expression of miR-17-5p and thioredoxin-interacting protein (TXNIP) were detected in the pancreas of DM mice. Pancreatic β-cell line INS-1 subjected to different concentrations of glucose was used in in vitro experiments. Results: Compared with control mice, glucose tolerance deficit, elevated blood glucose level, and decreased pancreatic islet size, were presented in DM mice, which was associated with a downregulation of miR-17-5p. Importantly, exogenous miR-17-5p alleviated pancreas injury, and consequently improved glucose tolerance and decreased blood glucose in DM mice. In vitro experiments showed that high glucose decreased miR-17-5p expression and impaired insulin secretion in INS-1 cells. Mechanistically, miR-17-5p inhibited the expression of TXNIP and NLRP3 inflammasome activation, and thus decreased pancreatic β-cell pyroptosis. Conclusion: Our results demonstrated that miR-17-5p improves glucose tolerance, and pancreatic β-cell function and inhibits TXNIP/NLRP3 inflammasome pathway-related pyroptosis in DM mice.

| S-EPMC8645844 | biostudies-literature

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Project description:Sepsis-induced myocardial dysfunction (SMD) is the major cause of death in sepsis. Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3)-mediated pyroptosis contributes to the occurrence and development of SMD. Although Apelin confers direct protection against SMD, the potential mechanisms remain unclear. This study aimed to determine whether Apelin protects against SMD via regulation of NLRP3-mediated pyroptosis of cardiomyocytes. Experimental SMD was induced in wild-type (WT) control mice and Apelin knockout (Apelin-/-) mice by cecal ligation and puncture (CLP). Neonatal mouse cardiomyocytes (NMCs) were treated with lipopolysaccharide (LPS) to simulate the physiological environment of SMD in vitro. The expression of Apelin was greatly decreased in the plasma from septic patients and septic mouse heart. Knockout of Apelin aggravated SMD, evidenced by decreased cardiac function, and increased cardiac fibrosis and NLRP3 inflammasome and pyroptosis levels in CLP-treated Apelin-/- mice compared with WT mice. Overexpression of Apelin activated the AMPK pathway and thereby inhibited NLRP3 inflammasome-mediated pyroptosis of NMCs induced by LPS in vitro These protective effects were partially abrogated by AMPK inhibitor. In conclusion, Apelin attenuated SMD by inhibiting NLRP3-mediated pyroptosis via activation of the AMPK pathway. Apelin may serve as a promising therapeutic target for SMD.

| S-EPMC10864914 | biostudies-literature

Citric acid, an ovarian cancer metabolite, induces pyroptosis via caspase-4/TXNIP-NLRP3-GSDMD pathway in ovarian cancer

Project description:Malignant tumors display profound changes in cellular metabolism, yet how these altered metabolites affect the development and growth of tumors is not fully understood. Here, we used metabolomics to analyze the metabolic profile differences in ovarian cancer, and found that citric acid (CA) is the most significantly downregulated metabolite. Recently, CA has been reported to inhibit the growth of a variety of tumor cells, but whether it is involved in pyroptosis of ovarian cancer and its potential molecular mechanisms still remains to be further investigated. Here, we demonstrated that CA inhibits the growth of ovarian cancer cells in a dose-dependent manner. RNA-seq analysis revealed that CA significantly promoted the expression of thioredoxin interacting protein (TXNIP) and caspase-4 (CASP4). Morphologic examination by transmission electron microscopy indicated that CA-treated ovarian cancer cells exhibited typical pyroptosis characteristics. Further mechanistic analyses showed that CA facilitates pyroptosis via CASP4/TXNIP-NLRP3-Gesdermin-d (GSDMD) pathway in ovarian cancer. This study elucidated that CA induces ovarian cancer cell death through classical and non-classical pyroptosis pathways, which may be beneficial as an ovarian cancer therapy.

2022-08-01 | GSE189851 | GEO

Downregulation of macrophage migration inhibitory factor attenuates NLRP3 inflammasome mediated pyroptosis in sepsis-induced AKI.

Project description:Sepsis-induced AKI (acute kidney injury) is considered an inflammation-related disease with high mortality. LPS-induced (Lipopolysaccharide) TLR4-NFκB pathway activation plays an important role in sepsis-induced AKI. Pyroptosis closely associated with inflammation response includes inflammasome formation, caspase1 activation and GSDMD N-terminal fragment cleavage that leads to cell membrane rupture and cell death, which may be related to the pathogenesis of sepsis-induced AKI. MIF (Macrophage migration inhibitory factor), associated with inflammation response, has been proved as a biomarker of sepsis, and perhaps regulate pyroptosis in sepsis-induced AKI. In this study, we focus on investigating the mechanism of MIF promoting pyroptosis in sepsis-induced AKI. MIF and pyroptosis-related proteins were up-regulated in kidney tissue of mice with CLP (cecum ligation puncture) surgery and in LPS-injured human kidney-2 (HK-2) cells. NLRP3 was down-regulated following the suppression of MIF topoisomerase activity by ISO-1 in kidney tissue of CLP mice. Knockdown of MIF alleviated NLRP3 inflammasome mediated pyroptosis in LPS-injured HK-2 cells. Meanwhile, we noted that phosphorylation of p65 was down-regulated by knockdown of MIF. Up-regulation of NLRP3 in response to LPS stimulation could be reversed by JSH-23, an inhibitor of NFκB pathway, but MIF was not affected. In conclusion, up-regulation of MIF in sepsis-induced AKI shows a renal damaged effect that aggravates NLRP3 inflammasome mediated cell pyroptosis through promoting phosphorylation of p65. This study demonstrated a novel mechanism of MIF regulating NLRP3 inflammasome mediated pyroptosis in sepsis-induced AKI.

| S-EPMC8844278 | biostudies-literature

miRNA-141 Induced Pyroptosis in Intervertebral Disk Degeneration by Targeting ROS Generation and Activating TXNIP/NLRP3 Signaling in Nucleus Pulpous Cells.

Project description:The role and mechanism of pyroptosis in intervertebral disk (IVD) degeneration are unclear. MicroRNAs (miRNAs) regulate the viability and function of nucleus pulposus cells (NPCs) in IVDs and are related to pyroptosis. We performed microarray analyses of normal and degenerated nucleus pulposus (NP) to assess the role of pyroptosis and identify key miRNAs in IVD degeneration. We also evaluated the underlying mechanism of miRNA-mediated pyroptosis in NPCs. In addition, we demonstrated the preventative effects of miRNAs on IVD degeneration in a rat model. The levels of the pyroptosis-related proteins cleaved caspase-1, N-terminal gasdermin D (GSDMD), interleukin (IL)-1β, and IL-18 in the degenerative NP were significantly higher than those in the normal NP. miRNA-141 was significantly upregulated in the degenerated NP. miR-141 mimic suppressed the matrix synthesis function of NPCs. By contrast, reactive oxygen species (ROS) generation, and the expression of TXNIP and NLRP3 were significantly downregulated by an miR-141 inhibitor. Furthermore, the miRNA-141 inhibitor prevented the degeneration of IVDs in vivo. Our findings suggest that miRNA-141 induces pyroptosis and extracellular matrix (ECM) catabolism in NPCs by increasing ROS generation and activating TXNIP/NLRP3 signaling. miRNA-141-regulated pyroptosis may be a novel therapeutic target for IVD degeneration.

| S-EPMC7487322 | biostudies-literature

MFG-E8 alleviates intervertebral disc degeneration by suppressing pyroptosis and extracellular matrix degradation in nucleus pulposus cells via Nrf2/TXNIP/NLRP3 axis.

Project description:Intervertebral disc degeneration (IVDD) is a chronic age-related degenerative disease accompanied by complex pathophysiological mechanisms. Increasing evidence indicates that NLRP3 inflammasome mediated pyroptosis of nucleus pulposus (NP) cells displays an important role in the pathological progression of IVDD. Milk fat globule-EGF factor-8 (MFG-E8) is an endogenously secreted glycoprotein with beneficial effects of anti-inflammatory, antioxidant, and modulation of NLRP3 inflammasome. However, the effect of MFG-E8 on IVDD remains unclear. In this study, our purpose is to clarify the expression changes of MFG-E8 in the IVDD process and explore the role and mechanism of MFG-E8. We found that MFG-E8's expression was reduced in degraded nucleus pulposus tissues of humans and rats as well as hydrogen peroxide (H2O2)-treated NP cells. Exogenous supplementation of MFG-E8 could rescue H2O2-induced oxidative stress, mitochondrial dysfunction, and NLRP3 inflammasome activation and protect NP cells from pyroptosis and extracellular matrix (ECM) degradation. Mechanistically, Nrf2/TXNIP/NLRP3 axis plays a crucial role in MFG-E8-mediated suppression of the above-pathological events. In vivo, we established a rat intervertebral disc acupuncture model and found that MFG-E8 administration effectively alleviated IVDD development by imageological and histomorphological evaluation. Overall, our findings revealed the internal mechanisms underlying MFG-E8 regulation in NP cells and its intrinsic value for IVDD therapy.

| S-EPMC9018842 | biostudies-literature

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