Mouse Bone Marrow Mesenchymal Stem Cells Inhibit Sepsis-Induced Lung Injury in Mice via Exosomal SAA1

Zhou, Lv; Duan, Shuxian; Zhou, Miao; Gu, Minglu; Liu, Siyuan; Wang, Yan; Xia, Qing; Xu, Dun‐Feng; Mao, Yanfei; Dong, Wenwen; Jiang, Lai

doi:10.1021/acs.molpharmaceut.2c00542

Cited by 9 publications

(6 citation statements)

References 48 publications

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“…The SAA protein family is typically found in various inflammatory diseases and sepsis [ 102 , 103 , 104 , 105 ], particularly in exosomes [ 103 , 105 ]. For instance, exosomal SAA1 has been shown to be effective in treating lung injury caused by sepsis [ 105 , 106 ]. Exosomal SAA3 is associated with the induction of STAT3 signaling [ 107 ] and anti-inflammatory M2 polarization [ 108 ]; FGL-1 binds to and activates LAG-3, a regulatory protein on T cells, for immunotherapy [ 109 , 110 ] and anti-inflammation [ 111 ]; ORM2, also known as AGP2, can inhibit neutrophil migration in diabetic mice with sepsis [ 112 ]; NGP, specific for mouse neutrophils [ 113 ], exhibits sequence similarity to an antimicrobial protein CAMP [ 113 ] and demonstrates inflammation modulation [ 113 , 114 ].…”

Section: Discussionmentioning

confidence: 99%

Circulating Exosomes from Septic Mice Activate NF-κB/MIR17HG Pathway in Macrophages

Wu,

Rau,

et al. 2024

Biomedicines

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Circulating exosomes derived from polymicrobial sepsis contain various non-coding RNAs and proteins. Isobaric tags for a relative or absolute quantitation proteomic analysis of the exosomal content revealed 70 dysregulated proteins in the circulating exosomes from septic mice. Next-generation sequencing was used to profile the long non-coding RNA expression in primary cultured macrophages treated with exosomes obtained from the blood of septic C57BL/6 mice, and it was discovered that the nuclear factor-kappa B (NF-κB)/miR-17-92a-1 cluster host gene (MIR17HG) pathways were activated in the macrophages. The inhibition of MIR17HG expression by RNA interference resulted in significantly decreased cell viability. RNA pull-down assays of MIR17HG revealed that ten protein targets bind to MIR17HG. Interaction networks of proteins pulled down by MIR17HG were constructed using GeneMANIA, and their functions were mainly involved in ribonucleoprotein granules, type I interferons, the regulation of organelle assembly, the biosynthesis of acetyl coenzyme A, as a signal transducer and activator of transcription (STAT) protein phosphorylation, and mRNA splicing. Furthermore, RNA interference inhibited MIR17HG expression, resulting in significantly decreased cell survival. In conclusion, this work discovered considerable MIR17HG overexpression in macrophages treated with circulating exosomes from sepsis-affected animals. This study’s findings assist us in comprehending the role of exosomes in modulating inflammatory responses and mediating pathogenic pathways in macrophages during sepsis.

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Section: Discussionmentioning

confidence: 99%

Circulating Exosomes from Septic Mice Activate NF-κB/MIR17HG Pathway in Macrophages

Wu,

Rau,

et al. 2024

Biomedicines

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“…The lungs are the most vulnerable target organs in sepsis, and among patients with sepsis, approximately 40% of patients develop ALI (37). The mortality rate of ALI is as high as 30% to 40%, which greatly endangers human health (38).…”

Section: Discussionmentioning

confidence: 99%

HYDROGEN PREVENTS LIPOPOLYSACCHARIDE-INDUCED PULMONARY MICROVASCULAR ENDOTHELIAL CELL INJURY BY INHIBITING STORE-OPERATED Ca2+ ENTRY REGULATED BY STIM1/ORAI1

Li,

Chen,

Shu

et al. 2023

Shock

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Background Sepsis is a type of life-threatening organ dysfunction that is caused by a dysregulated host response to infection. The lung is the most vulnerable target organ under septic conditions. Pulmonary microvascular endothelial cells (PMVECs) play a critical role in acute lung injury (ALI) caused by severe sepsis. The impairment of PMVECs during sepsis is a complex regulatory process involving multiple mechanisms, in which the imbalance of calcium (Ca2+) homeostasis of endothelial cells is a key factor in its functional impairment. Our preliminary results indicated that hydrogen gas (H2) treatment significantly alleviates lung injury in sepsis, protects PMVECs from hyperpermeability, and decreases the expression of plasma membrane stromal interaction molecule 1 (STIM1), but the underlying mechanism by which H2 maintains Ca2+ homeostasis in endothelial cells in septic models remains unclear. Thus, the purpose of the present study was to investigate the molecular mechanism of STIM1 and Ca2+-release-activated- Ca2+ channel protein1 (Orai1) regulation by H2 treatment and explore the effect of H2 treatment on Ca2+ homeostasis in lipopolysaccharide (LPS)-induced PMVECs and LPS-challenged mice. Methods We observed the role of H2 on LPS-induced ALI of mice in vivo. The lung wet/dry (W/D) weight ratio, total protein in the bronchoalveolar lavage (BAL) fluid and Evans blue dye (EBD) assay were used to evaluate the pulmonary endothelial barrier damage of LPS-challenged mice. The expression of STIM1 and Orai1 were also detected using epifluorescence microscopy. Moreover, we also investigated the role of H2- rich medium in regulating PMVECs under LPS treatment, which induced injury similar to sepsis in vitro. The expression of STIM1 and Orai1 as well as the Ca2+ concentration in PMVECs were examined. Results In vivo, we found that H2 alleviated ALI of mice through decreasing lung W/D weight ratio, total protein in the BAL fluid and permeability of lung. In addition, H2 also decreased the expression of STIM1 and Orai1 in pulmonary microvascular endothelium. In vitro, LPS treatment increased the expression levels of STIM1 and Orai1 in PMVECs, while H2 reversed these changes. Furthermore, H2 ameliorated Ca2+ influx under sepsis-mimicking conditions. Treatment with the sarco/endoplasmic reticulum Ca2+ adenosine triphosphatase (SERCA) inhibitor, thapsigargin (TG), resulted in a significant reduction in cell viability as well as a reduction in the expression of junctional proteins, including VE-cadherin and occludin. Treatment with the store-operated Ca2+ entry (SOCE) inhibitor, YM-58483 (BTP2), increased the cell viability and expression of junctional proteins. Conclusions The present study suggested that H2 treatment alleviates LPS-induced PMVEC dysfunction by inhibiting SOCE mediated by STIM1 and Orai1 in vitro and in vivo.

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“…Adipose-derived stem cell exosomes inhibit in ammation and oxidative stress in lipopolysaccharide acute kidney injury [19]. Mouse bone marrow mesenchymal stem cells secreted serum amyloid A1 protein in exosomes to inhibit sepsis-induced lung injury in mice [20]. On the contrary, serum exosome-derived miR-155 stimulated macrophage proliferation and in ammation in lung tissue and mediated septic lung injury [21].…”

Section: Read Full Licensementioning

confidence: 99%

Exosomes derived from Schistosoma japonicum Cystatin treated macrophages attenuated CLP-induced sepsis in mice

Huang

Qian

et al. 2022

Preprint

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Background Sepsis is a disease caused by multiple microbial infections resulting in excessive immune activation and multiple organ failure. Schistosoma japonicum cystatin (Sj-Cys) is a cysteine protease inhibitor and strong immunomodulator that stimulates M2 macrophages and alleviates inflammatory damage caused by sepsis. We would like to investigate whether exosomes derived from Sj-Cys treated macrophages convey the anti-inflammatory responses to mice with sepsis. Methods RAW264.7 macrophages were treated with rSj-Cys (2 µg/mL) for 48 h, the exosomes were obtained from the cell culture supernatant by ultracentrifugation and identified by transmission electron microscope, flow cytometry and Western blot assay. Sepsis was induced in BALB/c mice by cecal ligation and puncture (CLP). The mice with CLP-induced sepsis were treated with exosomes via intraperitoneal injection (10 µg/mouse). The therapeutic effect of exosomes on sepsis was assessed by observing the survival rate of mice up to 72 hours after CLP surgery and by measuring serum levels of inflammatory cytokines, liver/kidney damage biomarkers alanine aminotransferase (ALT), aspartate aminotransferase (AST)/urea nitrogen (BUN) and creatinine (Cr) in sera and observing pathological changes in tissue sections. The tissue levels of M1(iNOS), M2 (Arg-1) macrophage surface markers and TRL2/MyD88 were measured to explore possible mechanisms. Results Exosomes derived from Sj-Cys-treated macrophages exhibited significant therapeutic effect on CLP-induced sepsis in mice with prolonged survival rate and less damage of critical organs by down-regulating the pro-inflammatory factors TNF-α and IL-6 and up-regulating the anti-inflammatory factor TGF-β. The therapeutic effect of exosomes is associated with macrophage polarization from M1 (iNOS+) to M2 (Arg-1+) in infected tissues via down-regulating TRL2/MyD88 inflammatory pathway. Conclusions Exosomes derived from Sj-Cys-treated macrophages attenuated sepsis in mice through promoting macrophage polarization from M1 to M2 and reducing inflammatory responses, possibly via down-regulating TLR2/MyD88 inflammatory signaling pathway.

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Mouse Bone Marrow Mesenchymal Stem Cells Inhibit Sepsis-Induced Lung Injury in Mice via Exosomal SAA1

Cited by 9 publications

References 48 publications

Circulating Exosomes from Septic Mice Activate NF-κB/MIR17HG Pathway in Macrophages

Circulating Exosomes from Septic Mice Activate NF-κB/MIR17HG Pathway in Macrophages

HYDROGEN PREVENTS LIPOPOLYSACCHARIDE-INDUCED PULMONARY MICROVASCULAR ENDOTHELIAL CELL INJURY BY INHIBITING STORE-OPERATED Ca2+ ENTRY REGULATED BY STIM1/ORAI1

Exosomes derived from Schistosoma japonicum Cystatin treated macrophages attenuated CLP-induced sepsis in mice

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