Abstract 305: Tumor Necrosis Factor-α p75 Receptor, Satellite-Cell Survival, Activation and Muscle Regeneration

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
David A Goukassian ◽  
Tengiz Tkebuchava ◽  
Evelyn Bord ◽  
Marcy Silver ◽  
Cynthia Curry ◽  
...  
Keyword(s):  
Satellite Cells ◽  
Muscle Regeneration ◽  
Mononuclear Cells ◽  
Critical Role ◽  
Fold Increase ◽  
Vegf Mrna ◽  
Gene Target ◽  
Ischemic Tissue ◽  
Tnf Α ◽  
P75 Receptor

Aging is a risk factor for ischemic diseases. TNF-α, a pro-inflammatory cytokine, is expressed in ischemic tissues and is known to modulate angiogenesis. Little is known about the role of TNF-α receptors (TNFR1/p55 and TNFR2/p75) in angiogenic signaling and muscle regeneration. We studied neovascularization in the hind limb ischemia (HLI) model in young and old TNFR2/p75 knockout (p75KO) and wild type (WT) age-matched controls. Between days 7–10 post-HL surgery 100% of old p75KOs experienced auto-amputation of the operated limbs, whereas none of the age-matched WT mice exhibited HL necrosis. Poor blood flow recovery in p75KOs was associated with decreased capillary density and significant reduction in the expression of VEGF mRNA transcripts in ischemic tissue. Compared to presurgery, on days 1–10 post-HL surgery there was 6–10-fold increase in the number of satellite-cells (embrionic NCAM staining) in WT mice, whereas in p75KOs after day 1 through day 10 satellite cells were not detecable. Indeed, p75KO tissue showed increased and prolonged (via day 10) inflammation - neutrophil (MPO-1) and macrophage (F/480) infiltration. Transplantation of WT/GFP (+) BM mononuclear cells into γ-irradiated p75KOs one month prior to HL surgery prevented limb loss, suggesting that ischemia-induced neovascularization and mobilization of BM-derived cells is mediated, at least in part, via TNFR2/p75 expressed in BM-derived cells. In the same BM transplantation model we evaluated the rate of proliferation (Ki67 + cells) of resident GFP (−) vs BM-derived GFP (+) cells. We found that in both WT and p75KO ischemic tissue Ki67 (+) cells almost exclusively were GFP (+), indicating that only BM-derived cells proliferate in the ischemic tissue. Interestingly, Ki67/GFP (+) cells started to appear in WT tissue by day 3 through day 21, whereas in p75KO tissue first proliferative activity was detected on day 28, suggesting extremely delayed recovery and regenaration in p75KO tissue. Our study suggests that, signaling through p75 receptor is required for collateral vessel development in ischemia-induced neovascularization as well as plays a critical role in muscle regeneration and suggest a potential gene target, which could be used to improve the repair of ischemic tissue in adults.

scholarly journals Combined Stimulation with Interleukin-18 and Interleukin-12 Potently Induces Interleukin-8 Production by Natural Killer Cells

2017 ◽  
Vol 9 (5) ◽  
pp. 511-525 ◽  
Author(s):  
Sophie M. Poznanski ◽  
Amanda J. Lee ◽  
Tina Nham ◽  
Evan Lusty ◽  
Margaret J. Larché ◽  
...  
Keyword(s):  
Immune Response ◽  
Nk Cells ◽  
Natural Killer ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Nk Cell ◽  
Critical Role ◽  
Interleukin 12 ◽  
Tnf Α ◽  
Ifn Γ

The combination of interleukin (IL)-18 and IL-12 (IL-18+IL-12) potently stimulates natural killer (NK) cells, triggering an innate immune response to infections and cancers. Strategies exploiting the effects of IL-18+IL-12 have shown promise for cancer immunotherapy. However, studies have primarily characterized the NK cell response to IL-18+IL-12 in terms of interferon (IFN)-γ production, with little focus on other cytokines produced. IL-8 plays a critical role in activating and recruiting immune cells, but it also has tumor-promoting functions. IL-8 is classically produced by regulatory NK cells; however, cytotoxic NK cells do not typically produce IL-8. In this study, we uncover that stimulation with IL-18+IL-12 induces high levels of IL-8 production by ex vivo expanded and freshly isolated NK cells and NK cells in peripheral blood mononuclear cells. We further report that tumor necrosis factor (TNF)-α, produced by NK cells following IL-18+IL-12 stimulation, regulates IL-8 production. The IL-8 produced is in turn required for maximal IFN-γ and TNF-α production. These findings may have important implications for the immune response to infections and cancer immunotherapies. This study broadens our understanding of NK cell function and IL-18+IL-12 synergy by uncovering an unprecedented ability of IL-18+IL-12-activated peripheral blood NK cells to produce elevated levels of IL-8 and identifying the requirement for intermediates induced by IL-18+IL-12 for maximal cytokine production following stimulation.

Abstract 14810: Sam68 Promotes Nf-kb Signaling and Inflammation and Impedes the Recovery of Arterial Injury

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Shuling Han ◽  
Junlan Zhou ◽  
Gangjian Qin
Keyword(s):  
Inflammatory Cytokines ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Vascular Inflammation ◽  
Critical Role ◽  
Inflammatory Cells ◽  
Peritoneal Macrophages ◽  
Post Injury ◽  
Raw264.7 Macrophages ◽  
Tnf Α

Background: The role of Src-associated in mitosis 68 kDa (Sam68) protein in cardiovascular biology has not been studied. A recent report suggests that Sam68 suppresses TNF-α-mediated NF-kB activation. Since NF-kB plays a critical role in vascular inflammation and injury via generation of inflammatory cytokines and recruitment of inflammatory cells, we sought to dissect the molecular mechanism by which Sam68 regulates NF-kB signaling and its functional significance during vascular injury. Methods & Results: The endothelial denudation injury was induced in the carotid arteries of Sam68-null (Sam68 -/- ) and WT mice. Sam68 -/- mice displayed an accelerated re-endothelialization ( P <0.05 at day 5 post-injury) and attenuated neointima formation (by 2.2 folds, P <0.05, at day 14), which was associated with a reduced number of macrophages and lowered expression of pro-inflammatory cytokines (i.e., TNF-alpha, MCP-1 and IL-6) in the injured vessels. In cultured Raw264.7 macrophages, knockdown of Sam68 resulted in a significant reduction in the TNF-α-induced expression of TNF-α, MCP-1, and IL-6 and in the level of nuclear phospho-p65, which indicates attenuated NF-kB activation. These results were confirmed in peritoneal macrophages and macrophages differentiated from bone-marrow mononuclear cells of Sam68 -/- and WT mice. To identify molecular mechanisms, Raw264.7 cells were treated with TNF-α and Vehicle, followed by Sam68 co-immunoprecipitation and mass-spectrometric identification of the Sam68-interacting proteins. We found that TNF-α treatment results in altered interactions of Sam68 with 22 cytosolic, cytoskeletal, and nuclear proteins. Further experiments are under way to validate their involvement in the NF-kB signaling. Conclusions: Our results for the first time suggest that Sam68 promotes pro-inflammatory response in injured arteries and impedes recovery, and this effect may be partially attributable to the exaggerated NF-kB activity.

Abstract 124: Sam68 Impedes the Recovery of Arterial Injury by Augmenting Inflammatory Response

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Shuling Han ◽  
Junlan Zhou ◽  
Baron T Arnone ◽  
Dauren Biyashev ◽  
Chan Boriboun ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Cytokines ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Vascular Inflammation ◽  
Critical Role ◽  
Inflammatory Cells ◽  
Peritoneal Macrophages ◽  
Raw264.7 Macrophages ◽  
Tnf Α

Background: The role of Src-associated in mitosis 68 kDa (Sam68) in cardiovascular biology has not been studied. A recent report suggests that Sam68 suppresses TNF-α-induced NF-κB activation. Since NF-κB plays a critical role in vascular inflammation and injury via generation of inflammatory cytokines and recruitment of inflammatory cells, we sought to dissect the mechanism by which Sam68 regulates NF-κB signaling and its functional significance during vascular injury. Methods & Results: The endothelial denudation injury was induced in the carotid arteries of Sam68-/- and WT mice. Sam68-/- mice displayed an accelerated re-endothelialization and attenuated neointima hyperplasia, which was associated with a reduced number of macrophages and lowered expression of pro-inflammatory cytokines (i.e., TNF-α, IL-1β and IL-6) in the injured vessels. Importantly, the ameliorated vascular remodeling was recapitulated in WT mice after transplantation of bone marrow (BM) from Sam68-/- mice, suggesting beneficial role was attributed largely to BM-derived inflammatory cells. In cultured Raw264.7 macrophages, knockdown of Sam68 resulted in a significant reduction in the TNF-α-induced expression of TNF-α, IL-1β, and IL-6 and in the level of nuclear phospho-p65, indicating an attenuated NF-κB activation. These results were confirmed in peritoneal macrophages and macrophages differentiated from BM mononuclear cells of Sam68-/- and WT mice. To identify molecular mechanisms, Raw264.7 cells were treated with TNF-α and Vehicle, followed by Sam68 co-immunoprecipitation and mass-spec identification of Sam68-interacting proteins. Specifically, TNF-α treatment results in altered interactions of Sam68 with Filamin A (FLNA), a cytoskeleton protein known to be involved in NF-κB activation. Loss- and gain-of-function of Sam68 and FLNA suggest their mutual dependence in NF-κB activation and pro-inflammatory cytokine expression, and Sam68 is required for TRAF2-FLNA interaction. Conclusions: Our results for the first time suggest that Sam68 promotes pro-inflammatory response in injured arteries and impedes recovery, and this effect is attributed, in part, to the exaggerated NF-κB activity via Sam68-FLNA interaction and consequent TRAF2 stabilization.

scholarly journals Loss of full-length dystrophin expression results in major cell-autonomous abnormalities in proliferating myoblasts

2021 ◽  
Author(s):  
Maxime RF Gosselin ◽  
Virginie Mournetas ◽  
Malgorzata Borczyk ◽  
Lukasz Bozycki ◽  
Michal Korostynski ◽  
...  
Keyword(s):  
Satellite Cells ◽  
Muscle Regeneration ◽  
Therapeutic Target ◽  
Critical Role ◽  
Full Length ◽  
Muscle Disease ◽  
Sterile Inflammation ◽  
Mouse Muscle ◽  
Primary Mouse ◽  
First Time

Background. Duchenne muscular dystrophy (DMD) is the most common inherited muscle disease that leads to severe disability and death in young men. DMD is caused by out-of-frame mutations in the largest known gene, which encodes dystrophin. The loss of DMD gene expression manifests in progressive degeneration and wasting of striated muscles aggravated by sterile inflammation. Current conventional treatments are palliative only, whereas experimental therapeutic approaches focus on the re-expression of dystrophin in myofibers. However, recent studies established that DMD pathology begins already in prenatal development prior to myofiber formation while, in adult muscle, it affects satellite (stem) cells and the proper development of myofibers. Regeneration defects that exacerbate muscle degeneration appear to be a good therapeutic target, as maintaining regeneration would counteract muscle wasting. It is also the only feasible treatment in advanced stages of the disease. Yet, it is unknown whether dystrophic myoblasts, the intermediary between satellite cells and myofibers and effectors of muscle growth and repair, are also affected. Therefore, we investigated whether DMD myoblasts show a dystrophic phenotype. Methods and Findings. Using a combination of transcriptomic, molecular, biochemical, and functional analyses we demonstrate, to our knowledge for the first time, convergent cell-autonomous abnormalities in primary mouse and human dystrophic myoblasts. In Dmdmdx mouse myoblasts lacking full-length dystrophin transcripts, expression of 170 other genes was significantly altered. Myod1 (p=2.9e-21) and key muscle genes controlled by MyoD (Myog, Mymk, Mymx, epigenetic regulators, ECM interactors, calcium signaling and fibrosis genes) were significantly downregulated. Gene ontology enrichment analysis indicated significant alterations in genes involved in muscle development and function. These transcriptomic abnormalities translated into increased proliferation (p=3.0e-3), reduced migration towards both sera-rich (p=3.8e-2) and cytokine-containing medium (p=1.0e-2), and significantly accelerated differentiation in 3D organotypic cultures. These altered myoblast functions are essential for muscle regeneration. The defects were caused by the loss of expression of full-length dystrophin as strikingly similar and not exacerbated alterations were also observed in dystrophin-null Dmdmdx-βgeo myoblasts. Furthermore, corresponding abnormalities were identified in human DMD primary myoblasts and in an established dystrophic mouse muscle (SC5) cell line, confirming universal, cross-species and cell-autonomous nature of this defect. Conclusions. These results, for the first time, demonstrate the disease continuum: DMD defects in satellite cells cause myoblast dysfunctions diminishing muscle regeneration, which is essential to counteract myofiber degeneration. Full-length dystrophins play a critical role in these processes. Contrary to the established belief, our data identify myoblasts as a novel and important therapeutic target for treatment of this lethal disease.

Abstract 317: Satellite Cells Influence Collateral Vessel Formation via Paracrine Effects

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Laura Hansen ◽  
Wenxue Liu ◽  
Giji Joseph ◽  
Daiana Weiss ◽  
W. Robert Taylor
Keyword(s):  
Smooth Muscle ◽  
Cell Migration ◽  
Satellite Cells ◽  
Critical Role ◽  
Fold Increase ◽  
Endothelial Cell Migration ◽  
Collateral Vessel ◽  
Paracrine Factors ◽  
Artery Disease

Satellite cells are myogenic cells that play a critical role in skeletal muscle repair. They serve as stem cells for muscles, remaining dormant in healthy muscle but activating upon injury resulting in increased proliferation and differentiation into myoblasts. Another key aspect of muscle regeneration is reestablishing vascular supply, but the role of satellite cells in this process is not well established though they are known to produce a number of potential paracrine signals. Thus we hypothesized that satellite cells promote vascular growth through paracrine signaling induced by activation following muscle injury or ischemic damage from diseases such as peripheral artery disease. Using a murine model of hind limb ischemia, we showed that satellite cells increased 3.4 fold (p<0.01) in response to ischemia. To determine if satellite cells produce paracrine factors, we used a co-culture system for migration and proliferation. Satellite cells freshly isolated from the ischemic limb led to a 3.5 fold increase in smooth muscle migration (p<0.0001) and a 1.3 fold increase (p<0.01) in smooth muscle proliferation. Additionally, cultured satellite cells increased endothelial cell migration 2.8 fold. These results demonstrate the satellite cells produce paracrine factors which can drive both smooth muscle and endothelial cell migration and proliferation which are required for the development of collateral vessels. To test the potential therapeutic capability of satellite cells, alginate encapsulated satellite cells were delivered in the hind limb ischemic model. Using a whole animal in vivo imager to track luciferase expression of the cells, we found the encapsulated cells were viable for up to 2 weeks. The mice that received satellite cells also had significantly increased perfusion (28%, p<0.05) at 2 weeks as measured by Laser Doppler imaging. In conclusion our studies have shown that satellite cells increase in response to ischemia, produce paracrine factors that increase vascular cell migration in vitro, and lead to functional increases in perfusion in vivo. We believe these results demonstrate the critical role satellite cells play in collateral vessel formation and may be a potential new therapeutic approach for treating peripheral artery disease.

scholarly journals Satellite cell proliferation and skeletal muscle hypertrophy

2006 ◽  
Vol 31 (6) ◽  
pp. 782-790 ◽  
Author(s):  
Gregory R. Adams
Keyword(s):  
Cell Proliferation ◽  
Satellite Cell ◽  
Satellite Cells ◽  
Muscle Hypertrophy ◽  
Mononuclear Cells ◽  
Close Association ◽  
Critical Role ◽  
Skeletal Muscle Hypertrophy ◽  
Muscle Loading ◽  
Satellite Cell Proliferation

Satellite cells are small, mononuclear cells found in close association with striated skeletal muscles cells (myofibers). These cells appear to function as reserve myoblasts. A critical role for these cells in the process of muscle regeneration following injury has been clearly established. In that role, satellite cells have been shown to proliferate extensively. Some of the progeny of these cells then fuse with each other to form replacement myofibers, whereas others return to quiescence, thereby maintaining this reserve population. In response to injury, activated satellite cells can also fuse with damaged but viable myofibers to promote repair and regeneration. It has also been observed that satellite cells are activated during periods of significantly increased muscle loading and that some of these cells fuse with apparently undamaged myofibers as part of the hypertrophy process. The observation that the inactivation of satellite cell proliferation prevents most of the hypertrophy response to chronic increases in loading has lead to the hypothesis that a limitation to the expansion of myofiber size is imposed by the number of myonuclei present. Recent evidence suggests that a potential limitation to muscle hypertrophy, in the absence of a reserve supply of myonuclei, may be the inability to sustain increases in ribosomes, thereby limiting translational capacity.

scholarly journals Platelet Microparticles Enriched in miR-223 Reduce ICAM-1-Dependent Vascular Inflammation in Septic Conditions

2021 ◽  
Vol 12 ◽  
Author(s):  
Bernadett Szilágyi ◽  
Zsolt Fejes ◽  
Ágnes Rusznyák ◽  
Ferenc Fenyvesi ◽  
Marianna Pócsi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Mononuclear Cells ◽  
Vascular Inflammation ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Human Coronary Artery ◽  
Peripheral Blood Mononuclear ◽  
Gene Target ◽  
Mirna Level ◽  
Tnf Α

In the process of sepsis, activated platelets shed microvesicles containing microRNAs (miRNAs), which can be internalized by distinct recipient cells in circulation, consequently eliciting a potent capability to regulate their cellular functions in different diseases. In the present study, activated human platelets transferring miR-223 into endothelial cells via platelet-derived microparticles (PMPs) was investigated in vitro during septic conditions with a proposed mechanism involving in downregulation of the enhanced expression of intercellular adhesion molecule-1 (ICAM-1). The uptake of PMPs encasing miR-223 and the adhesion of peripheral blood mononuclear cells (PBMCs) on human coronary artery endothelial cells (HCAECs) were observed by immunofluorescence microscopy upon co-culture with PMPs isolated from sepsis or control plasma. The expression of miR-223-3p and its gene target ICAM1 in HCAECs were quantified by RT-qPCR and ELISA after the cells were incubated with septic or control PMPs, whose levels were induced with thrombin-receptor activating peptide (TRAP). Leukocyte-depleted platelets (LDPs) from septic patients showed a decreased miR-223 level, while septic plasma and PMPs revealed an elevated miRNA level compared to control samples. Similarly, TRAP-activated LDPs demonstrated a reduced intracellular miR-223 expression, while increased levels in the supernatant and PMP isolates were observed vs. untreated samples. Furthermore, TNF-α alone resulted in decreased miR-223 and elevated ICAM1 levels in HCAECs, while PMPs raised the miRNA level that was associated with downregulated ICAM1 expression at both mRNA and protein levels under TNF-α treatment. Importantly, miR-223 was turned out not to be newly synthesized as shown in unchanged pre-miR-223 level, and mature miR-223 expression was also elevated in the presence of PMPs in HCAECs after transfection with Dicer1 siRNA. In addition, septic PMPs containing miR-223 decreased ICAM1 with a reduction of PBMC binding to HCAECs. In conclusion, septic platelets released PMPs carrying functional miR-223 lower ICAM1 expression in endothelial cells, which may be a protective role against excessive sepsis-induced vascular inflammation.

Local Adrenergic Nerves Regulate Diurnal Leukocyte Adhesion: Impact In Sickle Cell Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1099-1099
Author(s):  
Christoph Scheiermann ◽  
Yuya Kunisaki ◽  
Jungeun Jang ◽  
Dachuan Zhang ◽  
Andrew Chow ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Circadian Rhythms ◽  
Adhesion Molecule ◽  
Leukocyte Adhesion ◽  
Critical Role ◽  
Fold Increase ◽  
Leukocyte Recruitment ◽  
Leukocyte Infiltration ◽  
Cell Disease ◽  
Tnf Α

Abstract Abstract 1099 Leukocyte recruitment is a crucial component of immune homeostasis. The sequential multistep process leading to leukocyte migration is thought to be regulated on demand at the inflammatory site. Here, we show that broad systemic programs involving long-range signals from the sympathetic nervous system (SNS) delivered by adrenergic nerves regulate rhythmic recruitment of leukocytes in tissues. While oscillations in the numbers of circulating leukocytes ranged from 4.1 to 7.8 × 106 cells/ml blood (P<0.001) with a peak ∼5h after the onset of light (zeitgeber time, ZT5), numbers of extravascular leukocytes in skeletal muscle exhibited circadian fluctuations whose pattern ran in antiphase with that of blood, peaking at ZT13 (night) and reaching a trough at ZT5 (ZT5 / ZT13: 5.3 ± 0.3 / 7.3 ± 0.3 cells per 100 × 50 μm2 extravascular vessel segment, p<0.001). Investigations of leukocyte-endothelial cell interactions in real-time by multi-channel fluorescence intravital microscopy (MFIM) of the cremasteric muscle microvasculature revealed increased myeloid cell recruitment at night (1.7-fold enhanced adhesion, p<0.05). Migratory oscillations were implemented by local SNS fibers since unilateral neurectomy of the genitofemoral nerve (GFNx), the nerve that innervates this muscle, completely (100%) ablated the night increase in leukocyte recruitment, suggesting an essential role for local innervation of the tissue in this process. Bone marrow chimeras revealed that signals acting on β2 and β3 adrenoreceptors expressed by non-hematopoietic cells were responsible for circadian recruitment leading to fluctuations of intercellular cell adhesion molecule-1 (ICAM-1) expression on endothelial cells (1.7- and 2-fold increase at ZT13 in ICAM-1 mRNA and protein levels, p<0.001 and p<0.05 respectively). ICAM-1 plays a critical role in this activity since Icam1-deficient animals did not exhibit an apparent rhythm in leukocyte infiltration. GFNx also completely abolished the night increase of ICAM-1 expression providing a direct link between SNS input and leukocyte infiltration. Since circadian rhythms are synchronized by light we tested whether alterations in photic input by induction of experimental jetlag would be sufficient to modify rhythms in leukocyte recruitment to the cremaster muscle. Indeed, circadian rhythms in extravascular leukocyte numbers in the tissue and fluctuations of ICAM-1 expression were completely abolished after a 12h jetlag. Oscillations were mediated by the molecular clock since rhythms of leukocyte numbers in both blood and tissue ceased to exist in Bmal1−/− animals kept in constant darkness for three weeks, in contrast to normal rhythms observed in heterozygous and wild-type littermates. Remarkably, circadian rhythms in leukocyte recruitment persisted during inflammation. After administration of TNF-α, circadian rhythms in ICAM-1 expression (1.4-fold increase, p<0.05) and leukocyte recruitment remained apparent, with ZT13 showing significantly higher leukocyte infiltration than ZT5. In contrast, TNF-α-induced leukocyte infiltration (82%) and adhesion molecule expression were strongly dampened when mice were subjected to a jetlag. To test the relevance in a disease model, we evaluated mice with sickle cell disease (SCD), a genetic disorder in which leukocyte adhesion and activation play a critical role in acute vaso-occlusion. Intravital microscopy revealed an increase in the numbers of adherent and extravasated leukocytes when the experiment was performed at night. In addition, we observed a 2-fold increase in the interactions between circulating RBCs and adherent leukocytes mediated by enhanced β2 integrin (Mac-1) activity (1.9-fold, p<0.05) on leukocytes and resulting in a 31% reduction of the mean venular blood flow rates. Strikingly, the overall survival of SCD mice was significantly reduced in mice challenged at night compared to the daytime (mean survival night: 305 min, day: 489 min, p<0.05, Log rank test). In conclusion, these data suggest that circadian rhythms in leukocyte recruitment can influence disease outcome and provide a novel paradigm in the leukocyte adhesion cascade with the potential for time-based therapeutics in inflammatory diseases. Disclosures: No relevant conflicts of interest to declare.

Expression of ATF3 in mouse protects the liver against sepsis via inhibiting HMGB expression

2014 ◽  
Vol 2 (4) ◽  
pp. 288-299 ◽  
Keyword(s):  
Innate Immunity ◽  
Liver Tissue ◽  
Mononuclear Cells ◽  
Critical Role ◽  
Negative Regulator ◽  
Immunofluorescent Staining ◽  
Protective Effects ◽  
Tlr4 Signaling ◽  
Tnf Α ◽  
Sepsis Therapy

Lipopolysaccharides are components of Gram-negative enterobacteria that cause septic shock in mammals and triggers innate immunity mainly via TLR4 signaling. HMGB1 play a critical role in regulating innate immunity-induced sepsis. ATF3 is a negative regulator of TLR4 signaling and the mechanism of HMGB1 induced liver injury after sepsis are incompletely understood. In this study, we investigated the protective effects of ATF3 after LPS injection. Adult (4-6 months) C57/BL6 mice and ATF3 knockout mice were treated with a low dose of LPS (0.5 mg/kg, iv) for 6, 12 hrs. Liver enzymes and cytokines (TNF-α, IL-1β and IL-6) are assessed. The neutrophil and mononuclear cells in the liver tissue were examined using immunofluorescent staining. We found that serum HMGB1 levels were 8-fold higher in C57/BL6 mice with sepsis than ATF3 knockout with greater densities of neutrophils and mononuclear cells in the liver tissue, and higher levels of TNF-α, IL-1β and IL-6 in the circulation and liver tissue as well as associated with an increase in the mortality rate. In conclusion, upregulation of ATF3 contributes to the reduced release of HMGB1, and increased the survival rate of mice after LPS treated. Therefore, suppressing LPS-induced inflammation with ATF3 induction may be an important strategy for sepsis therapy.

Elevated level of circulatory sTLT1 induces inflammation through SYK/MEK/ERK signalling in coronary artery disease

2019 ◽  
Vol 133 (22) ◽  
pp. 2283-2299
Author(s):  
Apabrita Ayan Das ◽  
Devasmita Chakravarty ◽  
Debmalya Bhunia ◽  
Surajit Ghosh ◽  
Prakash C. Mandal ◽  
...  
Keyword(s):  
Risk Factors ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Chronic Inflammation ◽  
Ex Vivo ◽  
Human Subjects ◽  
Critical Role ◽  
Atherosclerotic Cardiovascular Disease ◽  
Tnf Α ◽  
Artery Disease

Abstract The role of inflammation in all phases of atherosclerotic process is well established and soluble TREM-like transcript 1 (sTLT1) is reported to be associated with chronic inflammation. Yet, no information is available about the involvement of sTLT1 in atherosclerotic cardiovascular disease. Present study was undertaken to determine the pathophysiological significance of sTLT1 in atherosclerosis by employing an observational study on human subjects (n=117) followed by experiments in human macrophages and atherosclerotic apolipoprotein E (apoE)−/− mice. Plasma level of sTLT1 was found to be significantly (P<0.05) higher in clinical (2342 ± 184 pg/ml) and subclinical cases (1773 ± 118 pg/ml) than healthy controls (461 ± 57 pg/ml). Moreover, statistical analyses further indicated that sTLT1 was not only associated with common risk factors for Coronary Artery Disease (CAD) in both clinical and subclinical groups but also strongly correlated with disease severity. Ex vivo studies on macrophages showed that sTLT1 interacts with Fcɣ receptor I (FcɣRI) to activate spleen tyrosine kinase (SYK)-mediated downstream MAP kinase signalling cascade to activate nuclear factor-κ B (NF-kB). Activation of NF-kB induces secretion of tumour necrosis factor-α (TNF-α) from macrophage cells that plays pivotal role in governing the persistence of chronic inflammation. Atherosclerotic apoE−/− mice also showed high levels of sTLT1 and TNF-α in nearly occluded aortic stage indicating the contribution of sTLT1 in inflammation. Our results clearly demonstrate that sTLT1 is clinically related to the risk factors of CAD. We also showed that binding of sTLT1 with macrophage membrane receptor, FcɣR1 initiates inflammatory signals in macrophages suggesting its critical role in thrombus development and atherosclerosis.

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