LILRB4 deficiency aggravates the development of atherosclerosis and plaque instability by increasing the macrophage inflammatory response via NF-κB signaling

2017 ◽  
Vol 131 (17) ◽  
pp. 2275-2288 ◽  
Author(s):  
Zhou Jiang ◽  
Juan-Juan Qin ◽  
Yaxing Zhang ◽  
Wen-Lin Cheng ◽  
Yan-Xiao Ji ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Diseases ◽  
Chronic Inflammatory Disease ◽  
Plaque Instability ◽  
Atherosclerotic Lesions ◽  
Bone Marrow Derived Cells ◽  
Underlying Mechanisms ◽  
Human And Mouse

Atherosclerosis is a chronic inflammatory disease. Leukocyte immunoglobulin-like receptor B4 (LILRB4) is associated with the pathological processes of various inflammatory diseases. However, the potential function and underlying mechanisms of LILRB4 in atherogenesis remain to be investigated. In the present study, LILRB4 expression was examined in both human and mouse atherosclerotic plaques. The effects and possible mechanisms of LILRB4 in atherogenesis and plaque instability were evaluated in LILRB4-/-ApoE-/- and ApoE-/- mice fed a high-fat diet (HFD). We found that LILRB4 was located primarily in macrophages, and its expression was up-regulated in atherosclerotic lesions from human coronary arteries and mouse aortic roots. LILRB4 deficiency significantly accelerated the development of atherosclerotic lesions and increased the instability of plaques, as evident by the increased infiltration of lipids, decreased amount of collagen components and smooth muscle cells. Moreover, LILRB4 deficiency in bone marrow derived cells promoted the development of atherosclerosis. In vivo and in vitro analyses revealed that the proinflammatory effects of LILRB4 deficiency were mediated by the increased activation of NF-κB signaling due to decreased src homolog 2 domain containing phosphatase (Shp) 1 phosphorylation. In conclusion, the present study indicates that LILRB4 deficiency promotes atherogenesis, at least partly, through reduced Shp1 phosphorylation, which subsequently enhances the NF-κB-mediated inflammatory response. Thus, targetting the ‘LILRB4-Shp1’ axis may be a novel therapeutic approach for atherosclerosis.

scholarly journals The Beneficial Effects of Morusin, an Isoprene Flavonoid Isolated from the Root Bark of Morus

2020 ◽  
Vol 21 (18) ◽  
pp. 6541
Author(s):  
Dong Wook Choi ◽  
Sang Woo Cho ◽  
Seok-Geun Lee ◽  
Cheol Yong Choi
Keyword(s):  
Inflammatory Diseases ◽  
Root Bark ◽  
Biological Processes ◽  
Functional Roles ◽  
Beneficial Effects ◽  
Biochemical Identification ◽  
Underlying Mechanisms ◽  
Clinical Potential

The root bark of Morus has long been appreciated as an antiphlogistic, diuretic and expectorant drug in Chinese herbal medicine, albeit with barely known targets and mechanisms of action. In the 1970s, the development of analytic chemistry allowed for the discovery of morusin as one of 7 different isoprene flavonoid derivatives in the root bark of Morus. However, the remarkable antioxidant capacity of morusin with the unexpected potential for health benefits over the other flavonoid derivatives has recently sparked scientific interest in the biochemical identification of target proteins and signaling pathways and further clinical relevance. In this review, we discuss recent advances in the understanding of the functional roles of morusin in multiple biological processes such as inflammation, apoptosis, metabolism and autophagy. We also highlight recent in vivo and in vitro evidence on the clinical potential of morusin treatment for multiple human pathologies including inflammatory diseases, neurological disorders, diabetes, cancer and the underlying mechanisms.

scholarly journals Koumine Suppresses IL-1β Secretion and Attenuates Inflammation Associated With Blocking ROS/NF-κB/NLRP3 Axis in Macrophages

2021 ◽  
Vol 11 ◽  
Author(s):  
Yufei Luo ◽  
Bojun Xiong ◽  
Haiping Liu ◽  
Zehong Chen ◽  
Huihui Huang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Inhibitory Effect ◽  
Receptor Protein ◽  
Mechanistic Study ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Underlying Mechanisms

Koumine (KM), one of the primary constituents of Gelsemium elegans, has been used for the treatment of inflammatory diseases such as rheumatoid arthritis, but whether KM impacts the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome remains unknown. This study aimed to explore the inhibitory effect of KM on NLRP3 inflammasome activation and the underlying mechanisms both in vitro using macrophages stimulated with LPS plus ATP, nigericin or monosodium urate (MSU) crystals and in vivo using an MSU-induced peritonitis model. We found that KM dose-dependently inhibited IL-1β secretion in macrophages after NLRP3 inflammasome activators stimulation. Furthermore, KM treatment efficiently attenuated the infiltration of neutrophils and suppressed IL-1β production in mice with MSU-induced peritonitis. These results indicated that KM inhibited NLRP3 inflammasome activation, and consistent with this finding, KM effectively inhibited caspase-1 activation, mature IL-1β secretion, NLRP3 formation and pro-IL-1β expression in LPS-primed macrophages treated with ATP, nigericin or MSU. The mechanistic study showed that, KM exerted a potent inhibitory effect on the NLRP3 priming step, which decreased the phosphorylation of IκBα and p65, the nuclear localization of p65, and the secretion of TNF-α and IL-6. Moreover, the assembly of NLRP3 was also interrupted by KM. KM blocked apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and its oligomerization and hampered the NLRP3-ASC interaction. This suppression was attributed to the ability of KM to inhibit the production of reactive oxygen species (ROS). In support of this finding, the inhibitory effect of KM on ROS production was completely counteracted by H2O2, an ROS promoter. Our results provide the first indication that KM exerts an inhibitory effect on NLRP3 inflammasome activation associated with blocking the ROS/NF-κB/NLRP3 signal axis. KM might have potential clinical application in the treatment of NLRP3 inflammasome-related diseases.

Rosuvastatin corrects oxidative stress and inflammation induced by LPS to attenuate cardiac injury by inhibiting the NLRP3/TLR4 pathway

2021 ◽  
Author(s):  
Guocheng Ren ◽  
Qiujie Zhou ◽  
Meili Lu ◽  
Hongxin Wang
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Response ◽  
Cardiac Injury ◽  
H9c2 Cells ◽  
Sod Activity ◽  
Lps Challenge ◽  
Pathway Activation ◽  
Underlying Mechanisms

The aim of the current study was to evaluate whether rosuvastatin was effective in attenuating cardiac injury in lipopolysaccharide(LPS)-challenged mice and H9C2 cells and identify the underlying mechanisms, focusing on the NLRP3/TLR4 pathway. Cardiac injury, cardiac function, apoptosis, oxidative stress, inflammatory response and the NLRP3/TLR4 pathway were evaluated in both in vivo and in vitro studies. LPS-induced cardiomyocytes injury was markedly attenuated by rosuvastatin treatment. Apoptosis was clearly ameliorated in myocardial tissue and H9C2 cells cotreated with rosuvastatin. In addition, excessive oxidative stress was present, as indicated by increases in MDA content, NADPH activity and ROS production and decreased SOD activity after LPS challenge. Rosuvastatin improved all the indicators of oxidative stress, with a similar effect to NAC(ROS scavenger). Notably, LPS-exposed H9C2 cells and mice showed significant NLRP3 and TLR4/NF-κB pathway activation. Administration of rosuvastatin reduced the increases in expression of NLRP3, ASC, pro-caspase-1, TLR4, and p65 and decreased the contents of TNF-α, IL-1β, IL-18 and IL-6, with a similar effect as MCC950 (NLRP3 inhibitor). In conclusion, inhibition of the inflammatory response and oxidative stress contributes to cardioprotection of rosuvastatin on cardiac injury induced by LPS, and the effect of rosuvastatin was achieved by inactivation of the NF-κB/NLRP3 pathway

Antiseptic effect of vicenin-2 and scolymoside from Cyclopia subternata (honeybush) in response to HMGB1 as a late sepsis mediator in vitro and in vivo

2015 ◽  
Vol 93 (8) ◽  
pp. 709-720 ◽  
Author(s):  
Wonhwa Lee ◽  
Eun-Kyung Yoon ◽  
Kyung-Min Kim ◽  
Dong Ho Park ◽  
Jong-Sup Bae
Keyword(s):  
Inflammatory Diseases ◽  
Umbilical Vein ◽  
High Mobility ◽  
Nuclear Factor Κb ◽  
Underlying Mechanisms ◽  
And Migration ◽  
Umbilical Vein Endothelial Cells ◽  
Factor Α

Cyclopia subternata is a medicinal plant commonly used in traditional medicine to relieve pain. In this study, we investigated the antiseptic effects and underlying mechanisms of vicenin-2 and scolymoside, which are 2 active compounds from C. subternata that act against high mobility group box 1 (HMGB1)-mediated septic responses in human umbilical vein endothelial cells (HUVECs) and mice. The antiseptic activities of vicenin-2 and scolymoside were determined by measuring permeability, neutrophil adhesion and migration, and activation of proinflammatory proteins in HMGB1-activated HUVECs and mice. According to the results, vicenin-2 and scolymoside effectively inhibited lipopolysaccharide-induced release of HMGB1, and suppressed HMGB1-mediated septic responses such as hyperpermeability, the adhesion and migration of leukocytes, and the expression of cell adhesion molecules. In addition, vicenin-2 and scolymoside suppressed the production of tumor necrosis factor-α and interleukin 6, and activation of nuclear factor-κB and extracellular regulated kinases 1/2 by HMGB1. Collectively, these results indicate that vicenin-2 and scolymoside could be a potential therapeutic agents for the treatment of various severe vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway.

Recombinant P-selectin glycoprotein ligand–1 directly inhibits leukocyte rolling by all 3 selectins in vivo: complete inhibition of rolling is not required for anti-inflammatory effect

Blood ◽  
2003 ◽  
Vol 101 (8) ◽  
pp. 3249-3256 ◽  
Author(s):  
Anne E. R. Hicks ◽  
Sarah L. Nolan ◽  
Victoria C. Ridger ◽  
Paul G. Hellewell ◽  
Keith E. Norman
Keyword(s):  
Inflammatory Response ◽  
Clinical Benefit ◽  
Inflammatory Diseases ◽  
Neutrophil Migration ◽  
Acute Inflammatory Response ◽  
Leukocyte Rolling ◽  
Selectin Ligand ◽  
Inflammatory Effect

AbstractSelectin-dependent leukocyte rolling is one of the earliest steps of an acute inflammatory response and, as such, contributes to many inflammatory diseases. Although inhibiting leukocyte rolling with selectin antagonists is a strategy that promises far-reaching clinical benefit, the perceived value of this strategy has been limited by studies using inactive, weak, or poorly characterized antagonists. Recombinant P-selectin glycoprotein ligand–1–immunoglobulin (rPSGL-Ig) is a recombinant form of the best-characterized selectin ligand (PSGL-1) fused to IgG, and is one of the best prospects in the search for effective selectin antagonists. We have used intravital microscopy to investigate the ability of rPSGL-Ig to influence leukocyte rolling in living blood vessels and find that it can reduce rolling dependent on each of the selectins in vivo. Interestingly, doses of rPSGL-Ig required to reverse pre-existing leukocyte rolling are 30-fold higher than those required to limit inflammation, suggesting additional properties of this molecule. In support of this, we find that rPSGL-Ig can bind the murine chemokine KC and inhibit neutrophil migration toward this chemoattractant in vitro.

scholarly journals Eosinophils and Macrophages within the Th2-Induced Granuloma: Balancing Killing and Healing in a Tight Space

2019 ◽  
Vol 87 (10) ◽  
Author(s):  
Anupama Ariyaratne ◽  
Constance A. M. Finney
Keyword(s):  
Immune Cells ◽  
Host Response ◽  
Inflammatory Diseases ◽  
Innate Immune ◽  
Mouse Strains ◽  
Dual Function ◽  
Underlying Mechanisms ◽  
Parasitic Worms

ABSTRACTGranuloma formation is a key host immune response generated to confine invading pathogens and limit extensive host damage. It consists of an accumulation of host immune cells around a pathogen. This host response has been extensively studied in the context of inflammatory diseases. However, there is much less known about Th2-type granulomas generated in response to parasitic worms. Based onin vitrodata, innate immune cells within the granuloma are thought to immobilize and kill parasites but also act to repair damaged tissue. Understanding this dual function is key. The two billion people and many livestock/wild animals infected with helminths demonstrate that granulomas are not effective at clearing infection. However, the lack of high mortality highlights their importance in ensuring that parasite migration/tissue damage is restricted and wound healing is effective. In this review, we define two key cellular players (macrophages and eosinophils) and their associated molecular players involved in Th2 granuloma function. To date, the underlying mechanisms remain poorly understood, which is in part due to a lack of conclusive studies. Most have been performedin vitrorather thanin vivo, using cells that have not been obtained from granulomas. Experiments using genetically modified mouse strains and/or antibody/chemical-mediated cell depletion have also generated conflicting results depending on the model. We discuss the caveats of previous studies and the new tools available that will help fill the gaps in our knowledge and allow a better understanding of the balance between immune killing and healing.

scholarly journals In Vitro and In Vivo Anti-Inflammatory Effects of Polyphyllin VII through Downregulating MAPK and NF-κB Pathways

Molecules ◽  
2019 ◽  
Vol 24 (5) ◽  
pp. 875 ◽  
Author(s):  
Chao Zhang ◽  
Chaoying Li ◽  
Xuejing Jia ◽  
Kai Wang ◽  
Yanbei Tu ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Raw264.7 Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Steroidal Saponin ◽  
In Vivo Models ◽  
Protein Levels ◽  
Anti Inflammatory ◽  
Underlying Mechanisms

Background: Polyphyllin VII (PP7), a steroidal saponin from Paris polyphylla, has been found to exert strong anticancer activity. Little is known about the anti-inflammatory property of PP7. In this study, the anti-inflammatory activity and its underlying mechanisms of PP7 were evaluated in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and in multiple animal models. Methods: The content of nitric oxide (NO) was determined by spectrophotometry. The levels of prostaglandin E2 (PGE2) and cytokines were measured by enzyme-linked immunosorbent assay (ELISA) assay. The mRNA expression of pro-inflammatory genes was determined by qPCR. The total and phosphorylated protein levels were examined by Western blotting. The in vivo anti-inflammatory activities were evaluated by using mouse and zebrafish models. Results: PP7 reduced the production of NO and PGE2 and the protein and mRNA expressions of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and enzymes (inducible NO synthase [iNOS], cyclooxygenase-2 [COX-2], and Matrix metalloproteinase-9 [MMP-9]) in LPS-induced RAW264.7 cells by suppressing the NF-κB and MAPKs pathways. Notably, PP7 markedly inhibited xylene-induced ear edema and cotton pellet-induced granuloma formation in mice and suppressed LPS and CuSO4-induced inflammation and toxicity in zebrafish embryos. Conclusion: This study demonstrates that PP7 exerts strong anti-inflammatory activities in multiple in vitro and in vivo models and suggests that PP7 is a potential novel therapeutic agent for inflammatory diseases.

scholarly journals Wnt2 Contributes to the Development of Atherosclerosis

2021 ◽  
Vol 8 ◽  
Author(s):  
Jinyu Zhang ◽  
Samuel Rojas ◽  
Sanjay Singh ◽  
Phillip R. Musich ◽  
Matthew Gutierrez ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Wnt Signaling Pathway ◽  
Chronic Inflammatory Disease ◽  
Aortic Endothelial Cells ◽  
Mesenchymal Transition ◽  
Atherosclerotic Lesions ◽  
Endothelial To Mesenchymal Transition

Atherosclerosis, is a chronic inflammatory disease, characterized by the narrowing of the arteries resulting from the formation of intimal plaques in the wall of arteries. Yet the molecular mechanisms responsible for maintaining the development and progression of atherosclerotic lesions have not been fully defined. In this study, we show that TGF-β activates the endothelial-to-mesenchymal transition (EndMT) in cultured human aortic endothelial cells (HAECs) and this transition is dependent on the key executor of the Wnt signaling pathway in vitro. This study presents the first evidence describing the mechanistic details of the TGF-β-induced EndMT signaling pathway in HAECs by documenting the cellular transition to the mesenchymal phenotype including the expression of mesenchymal markers α-SMA and PDGFRα, and the loss of endothelial markers including VE-cadherin and CD31. Furthermore, a short hairpin RNA (shRNA) screening revealed that Wnt2 signaling is required for TGF-β-mediated EndMT of HAECs. Also, we found that LDLR−/− mice fed on a high-fat western-type diet (21% fat, 0.2% cholesterol) expressed high levels of Wnt2 protein in atherosclerotic lesions, confirming that this signaling pathway is involved in atherosclerosis in vivo. These findings suggest that Wnt2 may contribute to atherosclerotic plaque development and this study will render Wnt2 as a potential target for therapeutic intervention aiming at controlling atherosclerosis.

Abstract 405: Deficiency of p38α MAPK in Macrophages Promotes Apoptosis and Plaque Necrosis in Advanced Murine Atherosclerotic Lesions

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Tracie A Seimon ◽  
Yibin Wang ◽  
Seongah Han ◽  
Takafumi Senokuchi ◽  
George Kuriakose ◽  
...  
Keyword(s):  
New York ◽  
Er Stress ◽  
Rhode Island ◽  
Inflammatory Diseases ◽  
Heart Association ◽  
Atherosclerotic Lesions ◽  
P38α Mapk ◽  
Induced Apoptosis

Endoplasmic reticulum (ER) stress occurs in macrophage-rich areas of advanced atheroscle-rotic lesions and contributes to macrophage apoptosis and subsequent plaque necrosis. Therefore, signaling pathways that alter ER stress-induced apoptosis may affect the development of advanced atherosclerosis. Here we show that Western diet-fed Apoe −/− mice deficient in macrophage p38α MAPK have a marked increase in apoptosis and plaque necrosis. We found a significant increase in the mean necrotic area in the p38α-deficient lesions (46,700 μm 2 versus 18,965 μm 2 in the control mice, p < 0.008). Quantification of the data revealed an approximate 51% increase in the percent of apoptotic cells in the p38α-deficient lesions. The macrophage-p38α-deficient lesions also exhibited a 30% decrease in collagen content and a 40% decrease in fibrous cap thickness. Consistent with our in vivo data, we found that ER stress-induced apoptosis in cultured macrophages was markedly accelerated under conditions of p38 inhibition, and this effect was further enhanced in the setting of insulin resistance. Mechanistic experiments revealed that p38 inhibition causes suppression of the pro-survival Akt pathway in vitro and in vivo . We found that inhibition of Akt with LY294002 enhances apoptosis under conditions of ER stress. Furthermore, expression of a constitutively active Akt, myristoylated-Akt, blocked the enhancement of apoptosis that occurred with p38 inhibition, but did not inhibit apoptosis induced by ER stress itself. In view of clinical trials exploring the use of p38 inhibitors in inflammatory diseases, our results raise the possibility that these drugs may promote plaque progression in subjects with advanced atherosclerotic lesions. This research has received full or partial funding support from the American Heart Association, AHA Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).

Inhibitory effects of epimedium herb water extract on the inflammatory response in vitro and in vivo

Planta Medica ◽  
2016 ◽  
Vol 81 (S 01) ◽  
pp. S1-S381
Author(s):  
YC Oh ◽  
YH Jeong ◽  
WK Cho ◽  
SJ Lee ◽  
JY Ma
Keyword(s):  
Inflammatory Response ◽  
Water Extract ◽  
Inhibitory Effects
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