scholarly journals SAP130 released by damaged tubule drives necroinflammation via miRNA-219c/Mincle signaling in acute kidney injury

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Lin-Li Lv ◽  
Cui Wang ◽  
Zuo-Lin Li ◽  
Jing-Yuan Cao ◽  
Xin Zhong ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Macrophage Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Kidney Injury ◽  
Novel Therapy ◽  
Tubular Cells ◽  
Immune Cell Activation ◽  
Dependent Mechanism

AbstractTubules injury and immune cell activation are the common pathogenic mechanisms in acute kidney injury (AKI). However, the exact modes of immune cell activation following tubule damage are not fully understood. Here we uncovered that the release of cytoplasmic spliceosome associated protein 130 (SAP130) from the damaged tubular cells mediated necroinflammation by triggering macrophage activation via miRNA-219c(miR-219c)/Mincle-dependent mechanism in unilateral ureteral obstruction (UUO) and cisplatin-induced AKI mouse models, and in patients with acute tubule necrosis (ATN). In the AKI kidneys, we found that Mincle expression was tightly correlated to the necrotic tubular epithelial cells (TECs) with higher expression of SAP130, a damaged associated molecule pattern (DAMP), suggesting that SAP130 released from damaged tubular cells may trigger macrophage activation and necroinflammation. This was confirmed in vivo in which administration of SAP130-rich supernatant from dead TECs or recombinant SAP130 promoted Mincle expression and macrophage accumulation which became worsen with profound tubulointerstitial inflammation in LPS-primed Mincle WT mice but not in Mincle deficient mice. Further studies identified that Mincle was negatively regulated via miR-219c-3p in macrophages as miR-219c-3p bound Mincle 3′-UTR to inhibit Mincle translation. Besides, lentivirus-mediated renal miR-219c-3p overexpression blunted Mincle and proinflammatory cytokine expression as well as macrophage infiltration in the inflamed kidney of UUO mice. In conclusion, SAP130 is released by damaged tubules which elicit Mincle activation on macrophages and renal necroinflammation via the miR-219c-3p-dependent mechanism. Results from this study suggest that targeting miR-219c-3p/Mincle signaling may represent a novel therapy for AKI.

scholarly journals Kidney-Gut crosstalk in acute kidney injury

Kidney360 ◽  
2021 ◽  
pp. 10.34067/KID.0007722020
Author(s):  
Sang Kyung Jo
Keyword(s):  
Acute Kidney Injury ◽  
Cell Activation ◽  
Immune Cell ◽  
Kidney Injury ◽  
Leaky Gut ◽  
Immune Cell Activation ◽  
Bidirectional Relationship ◽  
Prevention And Treatment

Bidirectional relationship exist between kidney and intestine during AKI. Kidney IRI provoked dysbiosis, immune cell activation and leaky gut while dysbiosis (as a whole) act as an important modifier of AKI severity. Targeting the intestine/microbiota might provide a new avenue for the prevention and treatment of AKI.

scholarly journals OX40L blockade protects against inflammation-driven fibrosis

2016 ◽  
Vol 113 (27) ◽  
pp. E3901-E3910 ◽  
Author(s):  
Muriel Elhai ◽  
Jérôme Avouac ◽  
Anna Maria Hoffmann-Vold ◽  
Nadira Ruzehaji ◽  
Olivia Amiar ◽  
...  
Keyword(s):  
Cell Activation ◽  
Immune Cell ◽  
Unmet Need ◽  
Inflammatory Cells ◽  
Industrialized Countries ◽  
Immune Cell Activation ◽  
Proinflammatory Mediators ◽  
Vessel Injury ◽  
Fibrotic Process

Treatment for fibrosis represents a critical unmet need, because fibrosis is the leading cause of death in industrialized countries, and there is no effective therapy to counteract the fibrotic process. The development of fibrosis relates to the interplay between vessel injury, immune cell activation, and fibroblast stimulation, which can occur in various tissues. Immunotherapies have provided a breakthrough in the treatment of immune diseases. The glycoprotein OX40–OX40 ligand (OX40L) axis offers the advantage of a targeted approach to costimulatory signals with limited impact on the whole immune response. Using systemic sclerosis (SSc) as a prototypic disease, we report compelling evidence that blockade of OX40L is a promising strategy for the treatment of inflammation-driven fibrosis. OX40L is overexpressed in the fibrotic skin and serum of patients with SSc, particularly in patients with diffuse cutaneous forms. Soluble OX40L was identified as a promising serum biomarker to predict the worsening of lung and skin fibrosis, highlighting the role of this pathway in fibrosis. In vivo, OX40L blockade prevents inflammation-driven skin, lung, and vessel fibrosis and induces the regression of established dermal fibrosis in different complementary mouse models. OX40L exerts potent profibrotic effects by promoting the infiltration of inflammatory cells into lesional tissues and therefore the release of proinflammatory mediators, thereafter leading to fibroblast activation.

Prevention of NF-κB activation in vivo by a cell-permeable NF-κB inhibitor peptide

2005 ◽  
Vol 289 (4) ◽  
pp. L536-L544 ◽  
Author(s):  
Ana L. Mora ◽  
John LaVoy ◽  
Martha McKean ◽  
Arlene Stecenko ◽  
Kenneth L. Brigham ◽  
...  
Keyword(s):  
Recombinant Protein ◽  
Stress Responses ◽  
Cell Activation ◽  
Immune Cell ◽  
Nuclear Translocation ◽  
Inflammatory Diseases ◽  
New Approach ◽  
Immune Cell Activation ◽  
A Cell

The NF-κB/Rel transcription factor family plays a central role in coordinating the expression of a variety of genes that regulate stress responses, immune cell activation, apoptosis, proliferation, differentiation, and oncogenic transformation. Interventions that target the NF-κB pathway may be therapeutic for a variety of pathologies, especially immune/inflammatory diseases. Using membrane translocating sequence (MTS) technology, we developed a cell-permeable dominant inhibitor of NF-κB activation, termed IκBα-(ΔN)-MTS. This molecule contains a 12-amino acid MTS motif attached to the COOH-terminal region of a nondegradable inhibitor protein [IκBα-(ΔN)]. The recombinant protein enters cells and localizes in the cytoplasm. Delivery of the IκBα-(ΔN)-MTS to cell lines and primary cells inhibited nuclear translocation of NF-κB proteins induced by cell activation. The protein also effectively inhibited NF-κB activation in vivo in two different animal models: NF-κB activation in response to skin wounding in mice and NF-κB activation in lungs after endotoxin treatment in sheep. Inhibition of NF-κB by the IκBα-(ΔN)-MTS in the endotoxin model attenuated physiological responses to endotoxemia. These data demonstrate that activation of NF-κB can be inhibited using a recombinant protein designed to penetrate into cells. This technology may provide a new approach to NF-κB pathway-targeted therapies.

scholarly journals Innate immune cell activation and epigenetic remodeling in symptomatic and asymptomatic atherosclerosis in humans in vivo

2016 ◽  
Vol 254 ◽  
pp. 228-236 ◽  
Author(s):  
Siroon Bekkering ◽  
Inge van den Munckhof ◽  
Tim Nielen ◽  
Evert Lamfers ◽  
Charles Dinarello ◽  
...  
Keyword(s):  
Cell Activation ◽  
Immune Cell ◽  
Innate Immune ◽  
Innate Immune Cell ◽  
Immune Cell Activation ◽  
Epigenetic Remodeling

scholarly journals Platelet-rich Plasma Enhanced MSCs Repair for Glycerin-induced Acute Kidney Injury via AKT/Rab27 Paracrine Pathway

2020 ◽  
Author(s):  
Cheng Ji ◽  
Jiahui Zhang ◽  
Hui Shi ◽  
wanzhu Liu ◽  
Fengtian Sun ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Kidney Injury ◽  
Mesenchymal Stem Cells ◽  
Renal Function ◽  
Platelet Rich Plasma ◽  
Kidney Injury ◽  
Human Umbilical Cord ◽  
Tubular Cells ◽  
Renal Tubular Cells

Abstract Background: Acute kidney injury (AKI) was defined by rapid deterioration of renal function, as a common complication in hospitalized patients. Among the recent therapeutic options, mesenchymal stem cells (MSCs) were considered a promising strategy for damaged tissues repair. Platelet rich plasma (PRP) regulates stromal cells to repair tissue damage through the release of growth factors. Here we proposed a possible therapeutic use of human umbilical cord mesenchymal stem cells stimulated by platelet-rich plasma (PRP-MSCs) in a murine model of acute renal injury generated by glycerin injection.Methods: In vivo, we constructed cisplatin-induced acute kidney injury rat models. On day 1 post injury, rat received a tail vein injection of 1×106 MSCs and 1×106 PRP-MSCs. All animals were sacrificed at Day 3 after glycerin injection. Renal function (serum BUN, Creatinine), histopathological structure changes and tubular cells apoptosis were evaluated. In vitro experiment, 50 μmol/L of glycerin treated NRK-52E for 12h were incubated with MSC or PRP-MSC for 24h in transwell co-culture system. Cells were harvested for apoptosis assay, immunofluorescence assay, western blot, and quantitative real-time polymerase chain reaction (qRT-PCR).Results: In vivo and vitro studies confirmed that the PRP induced YAP nucleus expression to promoting the proliferation and reinforces the stemness of MSCs, and stimulated the paracrine exosomes of MSCs by activating AKT/Rab27 signaling pathway to inhibiting the apoptosis of renal tubular cells. Conclusions: Our results revealed a novel potential use of PRP-MSCs as therapeutic strategy for acute kidney injury, highlighting the presence and role of the reno-protective factor PRP-MSCs.

scholarly journals miR-20a-5p is enriched in hypoxia-derived tubular exosomes and protects against acute tubular injury

2020 ◽  
Vol 134 (16) ◽  
pp. 2223-2234 ◽  
Author(s):  
Wenjuan Yu ◽  
Honghui Zeng ◽  
Junzhe Chen ◽  
Sha Fu ◽  
Qiuyan Huang ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Protective Effect ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Target Cells ◽  
Tubular Injury ◽  
Novel Therapy ◽  
Mitochondrial Functions

Abstract Exosomes have been shown to effectively regulate the biological functions of target cells. Here, we investigated the protective effect and mechanism of hypoxia-induced renal tubular epithelial cells (TECs)-derived exosomes on acute tubular injury. We found that in vitro hypoxia-induced tubular exosomes (Hy-EXOs) were protective in acute tubular injury by promoting TECs proliferation and improving mitochondrial functions. By using exosome miRNA sequencing, we identified miR-20a-5p was abundant and was a key mechanism for the protective effect of Hy-EXOs on tubular injury as up-regulation of miR-20a-5p enhanced but down-regulation of miR-20a-5p inhibited the protective effect of Hy-EXOs on tubular injury under hypoxia conditions. Further study in a mouse model of ischemia–reperfusion-induced acute kidney injury (IRI-AKI) also confirmed this notion as pre-treating mice with the miR-20a-5p agomir 48 h prior to AKI induction was capable of inhibiting IRI-AKI by lowering serum levels of creatinine and urea nitrogen, and attenuating the severity of tubular necrosis, F4/80(+) macrophages infiltration and vascular rarefaction. Mechanistically, the protective effect of miR-20a-5p on acute kidney injury (AKI) was associated with inhibition of TECs mitochondrial injury and apoptosis in vitro and in vivo. In conclusion, miR-20a-5p is enriched in hypoxia-derived tubular exosomes and protects against acute tubular injury. Results from the present study also reveal that miR-20a-5p may represent as a novel therapy for AKI.

scholarly journals OS12.4 In vivo dynamics and targeting of vessel co-option in glioma

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii23-iii23
Author(s):  
G Seano ◽  
A Griveau ◽  
S Shelton ◽  
S Krishnan ◽  
N Wang ◽  
...  
Keyword(s):  
Single Cell ◽  
Cell Activation ◽  
Immune Cell ◽  
Glioma Cells ◽  
Angiogenic Therapy ◽  
Immune Cell Activation ◽  
Anti Vegf ◽  
Oligodendrocyte Precursor ◽  
Wnt Inhibitors

Abstract BACKGROUND Gliomas comprise heterogeneous malignant glial and stromal cells. While blood vessel co-option is a potential mechanism to escape anti-angiogenic therapy, the relevance of glial phenotype in this process is unclear. MATERIAL AND METHODS Here, we intravitally study preclinical syngenetic models of glioma as well as patient-derived cells transplanted orthotopically. Moreover, we profoundly confirm our preclinical results with histological studies on patient specimens. RESULTS We show that Olig2+ oligodendrocyte precursor-like glioma cells invade by single-cell vessel co-option and preserve the blood-brain barrier (BBB). Conversely, Olig2-negative glioma cells form dense perivascular collections and promote angiogenesis and BBB breakdown, leading to innate immune cell activation. Experimentally, Olig2 promotes Wnt7b expression, a finding that correlates in human glioma profiling. Targeted Wnt7a/7b deletion or pharmacologic Wnt inhibition blocks Olig2+ glioma single-cell vessel co-option and enhances responses to temozolomide. Finally, Olig2 and Wnt7 become upregulated after anti-VEGF treatment in preclinical models and patients. CONCLUSION Here, we show that glioma is able to employ vessel co-option, i.e. the movement of tumor cells towards and along the pre-existing vasculature. Glioma oligodendrocyte-like (OPCL) cells express Wnt7 that is necessary for vessel co-option and Wnt inhibitors significantly improve survival with temozolomide. Moreover, we demonstrated that anti-VEGF-treatment of glioma selects for Olig2/Wnt7+ cells

scholarly journals Heme oxygenase-1 induction contributes to renoprotection by G-CSF during rhabdomyolysis-associated acute kidney injury

2011 ◽  
Vol 301 (1) ◽  
pp. F162-F170 ◽  
Author(s):  
Qingqing Wei ◽  
William D. Hill ◽  
Yunchao Su ◽  
Shuang Huang ◽  
Zheng Dong
Keyword(s):  
Acute Kidney Injury ◽  
Heme Oxygenase ◽  
Cell Injury ◽  
Kidney Injury ◽  
Heme Oxygenase 1 ◽  
Protective Effects ◽  
Tubular Cells ◽  
Renal Tubular Cells

Granulocyte colony-stimulating factor (G-CSF) is renoprotective during acute kidney injury (AKI) induced by ischemia and cisplatin nephrotoxicity; however, the underlying mechanism is not entirely clear. Rhabdomyolysis is another important clinical cause of AKI, due to the release of nephrotoxins (e.g., heme) from disrupted muscles. The current study has determined the effects of G-CSF on rhabdomyolysis-associated AKI using in vivo and in vitro models. In C57BL/6 mice, intramuscular injection of glycerol induced AKI, which was partially prevented by G-CSF pretreatment. Consistently, glycerol-induced renal tissue damage was ameliorated by G-CSF. In addition, animal survival following the glycerol injection was improved from ∼30 to ∼70% by G-CSF. In cultured renal tubular cells, hemin-induced apoptosis was also suppressed by G-CSF. Interestingly, G-CSF induced heme oxygenase-1 (HO-1, a critical enzyme for heme/hemin degradation and detoxification) in both cultured tubular cells and mouse kidneys. Blockade of HO-1 with protoporphyrin IX zinc(II) (ZnPP) could largely diminish the protective effects of G-CSF. Together, these results demonstrated the renoprotective effects of G-CSF in rhabdomyolysis-associated AKI. Notably, G-CSF may directly protect against tubular cell injury under the disease condition by inducing HO-1.

scholarly journals Structural and Clinical Correlates of a Periventricular Gradient of Neuroinflammation in Multiple Sclerosis

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000011700
Author(s):  
Emilie Poirion ◽  
Matteo Tonietto ◽  
François-Xavier Lejeune ◽  
Vito A.G. Ricigliano ◽  
Marine Boudot de la Motte ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cell Activation ◽  
Immune Cell ◽  
Innate Immune ◽  
Innate Immune Cell ◽  
Magnetization Transfer Ratio ◽  
Immune Cell Activation ◽  
Microstructural Damage ◽  
Ventricular Surface

Objectives:To explore in-vivo innate immune cell activation as a function of the distance from ventricular CSF in patients with Multiple Sclerosis (MS) using [18F]-DPA714 PET, and to investigate its relationship with periventricular microstructural damage, evaluated by magnetization transfer ratio (MTR), and with trajectories of disability worsening.Methods:Thirty-seven MS patients and nineteen healthy controls underwent MRI and [18F]-DPA714 TSPO dynamic PET, from which individual maps of voxels characterized by innate immune cell activation (DPA+) were generated. White matter (WM) was divided in 3mm-thick concentric rings radiating from the ventricular surface toward the cortex, and the percentage of DPA+ voxels and mean MTR were extracted from each ring. Two-year trajectories of disability worsening were collected to identify patients with and without recent disability worsening.Results:The percentage of DPA+ voxels was higher in patients compared to controls in the periventricular WM (p=6.10e-6), and declined with increasing distance from ventricular surface, with a steeper gradient in patients compared to controls (p=0.001). This gradient was found both in periventricular lesions and normal-appearing WM. In the total WM, it correlated with a gradient of microstructural tissue damage measured by MTR (rs=-0.65, p=1.0e-3). When compared to clinically stable patients, patients with disability worsening were characterized by a higher percentage of DPA+ voxels in the periventricular normal-appearing WM (p=0.025).Conclusions:Our results demonstrate that in MS the innate immune cell activation predominates in periventricular regions and associates with microstructural damage and disability worsening. This could result from the diffusion of pro-inflammatory CSF-derived factors into surrounding tissues.

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