scholarly journals ATF4 Involvement in TLR4 and LOX-1-Induced Host Inflammatory Response to Aspergillus fumigatus Keratitis

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Shuchao Zhang ◽  
Pingping Meng ◽  
Guibo Liu ◽  
Kuixiang Liu ◽  
Chengye Che
Keyword(s):  
Inflammatory Response ◽  
Aspergillus Fumigatus ◽  
Mouse Models ◽  
Oxidized Ldl ◽  
Ldl Receptor ◽  
Activating Transcription Factor 4 ◽  
Activating Transcription Factor ◽  
Intrastromal Injection ◽  
Host Inflammatory Response

Purpose. Activating transcription factor 4 (ATF4) is induced by various stressors. Here, we investigated the expression of ATF4 in the host inflammatory response to Aspergillus fumigatus (A. fumigatus) keratitis. Methods. A. fumigatus keratitis mouse models developed by intrastromal injection as well as corneal epithelium scratching were examined daily with a slit lamp microscope for corneal opacification and ulceration. Subsequent in vitro experimentation was carried out in human corneal epithelial cells (HCECs) as well as THP-1 macrophages infected with A. fumigatus. Inhibitors, including CLI-095, Poly (I), SCH772984, and SP600125, were used to assess the role of proteins like toll-like receptor 4 (TLR4), lectin-type oxidized LDL receptor 1 (LOX-1), extracellular signal-regulated kinases (ERK1/2), and c-Jun N-terminal kinase (JNK) in ATF4 expression as a response to A. fumigatus infection. This assessment was made in both mouse models and HCECs using western blot. Results. Compared to the controls, ATF4 was increased in corneas from two kinds of A. fumigatus keratitis models at 3 days after infection. ATF4 expression was upregulated with A. fumigatus conidia both in HCECs and THP-1 macrophages 16 hours after stimulation. Furthermore, ATF4 expression in response to A. fumigatus infection was shown to be dependent on TLR4 and LOX-1 expression, and ERK1/2 and JNK contributed to the expression of ATF4 in response to A. fumigatus. Conclusion. Our results clearly indicate that ATF4 was involved in the host antifungal immune response to A. fumigatus keratitis; expression was found to be dependent on TLR4, LOX-1 expression, and MAPKs pathway.

scholarly journals Ellagitannins of the fruit rind of pomegranate (Punica granatum) antagonize in vitro the host inflammatory response mechanisms involved in the onset of malaria

2010 ◽  
Vol 9 (1) ◽  
Author(s):  
Mario Dell'Agli ◽  
Germana V Galli ◽  
Michela Bulgari ◽  
Nicoletta Basilico ◽  
Sergio Romeo ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Punica Granatum ◽  
Host Inflammatory Response ◽  
Fruit Rind

Abstract 263: Role of Micro RNA-21 in Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Rihab E Hamed-Berair ◽  
Srinivas D Sithu ◽  
Nalinie Wickramasinghe ◽  
Jasmit Shah ◽  
Abhinav Agawral ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Oxidized Ldl ◽  
Ldl Receptor ◽  
Micro Rna ◽  
Limited Information ◽  
Micro Rnas ◽  
Late Apoptosis ◽  
Apoptosis And Inflammation

Micro RNAs (miR) are short non-coding RNAs that regulate several genes under pathophysiological conditions. Accumulating evidence suggest the involvement of miR in atherogenesis. However, limited information is available about atherogenic miR and the underling mechanisms by which miR affect atherogenesis. Our data shows that 12 weeks of western diet (WD) in LDL receptor-knockout (LDLR-KO) mice upregulated 99 and downregulated 50 miR in the aorta. Among the 41 differentially expressed miR associated with macrophage inflammation and apoptosis, expression of micro RNA-21 (miR-21) was increased by 1.4-fold (P<0.05). WD also increased the expression of miR-21 by 1.5-fold in bone marrow derived macrophages (BMDM). In vitro , LDL, oxidized LDL, acetylated LDL and LPS induced miR-21 by 2-3-fold (P<0.05) and down regulated its target protein PDCD4 in BMDM. Basally, miR-21 deficient BMDM showed increased secretion of IL-6, IL-9 and CXCL-2,-3,-4, and -10 (P<0.05)); and increased early and late apoptosis (2-3-fold, P<0.05). We also observed 40% decrease in the survival of F4/80+ cells during differentiation of bone marrow derived cells isolated from miR-21-KO mice. Stimulation of miR-21-KO BMDM with LPS significantly increased the activation of NF-κB and enhanced the secretion of several pro-inflammatory cytokines including TNFα, IL-6, IL-12 and CXCL-2 (2-10 fold; P<0.05); interferon gamma+LPS polarized the macrophages to pro-inflammatory M1 phenotype (increased expression of CD11c and CD86). Staurosporin and oxidized lipids derived aldehyde 4-hydroxynonenal significantly increased both early and late apoptosis of miR-21-KO BMDM (2-4-fold, P<0.05). This was accompanied by increased cleavage of caspase -3, -7 and -9. Transplantation of bone marrow cells from miR-21-KO into LDLR-KO mice, followed by 12 weeks of WD increased the lesion formation (1.7-fold, P<0.05), apoptosis (3-fold, P<0.05) and necrosis (1.6-fold, P<0.05) in the aortic valve of the chimeric mice. Collectively, these data suggest that miR-21 prevents atherosclerosis, at least in parts, by preventing macrophage apoptosis and inflammation.

scholarly journals Pharmacological Disruption of Phosphorylated Eukaryotic Initiation Factor-2α/Activating Transcription Factor 4/Indian Hedgehog Protects Intervertebral Disc Degeneration via Reducing the Reactive Oxygen Species and Apoptosis of Nucleus Pulposus Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Junping Bao ◽  
Zhanyang Qian ◽  
Lei Liu ◽  
Xin Hong ◽  
Hui Che ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Intervertebral Disc Degeneration ◽  
Initiation Factor ◽  
Oxygen Species ◽  
Cell Degeneration ◽  
Activating Transcription Factor 4 ◽  
Tnf Α ◽  
Activating Transcription Factor ◽  
Transcription Factor 4

Excessive reactive oxygen species (ROS) and apoptosis in nucleus pulposus (NP) cells accelerate the process of intervertebral disc degeneration (IDD). Here, we integrated pathological samples and in vitro and in vivo framework to investigate the impact of phosphorylation of eukaryotic initiation factor-2α (eIF2α)/activating transcription factor 4 (ATF4)/Indian hedgehog (Ihh) signaling in the IDD. From the specimen analysis of the IDD patients, we found phosphorylated eIF2α (p-eIF2α), ATF4 and Ihh protein levels were positively related while the NP tissue went degenerative. In vitro, tumor necrosis factor (TNF)-α caused the NP cell degeneration and induced a cascade of upregulation of p-eIF2α, ATF4, and Ihh. Interestingly, ATF4 could enhance Ihh expression through binding its promoter region, and silencing of ATF4 decreased Ihh and protected the NP cells from degeneration. Moreover, ISRIB inhibited the p-eIF2α, which resulted in a suppression of ATF4/Ihh, and alleviated the TNF-α-induced ROS production and apoptosis of NP cells. On the contrary, further activating p-eIF2α aggravated the NP cell degeneration, with amplification of ATF4/Ihh and a higher level of ROS and apoptosis. Additionally, applying cyclopamine (CPE) to suppress Ihh was efficient to prevent NP cell apoptosis but did not decrease the ROS level. In an instability-induced IDD model in mice, ISRIB suppressed p-eIF2α/ATF4/Ihh and prevented IDD via protecting the anti-oxidative enzymes and decreased the NP cell apoptosis. CPE prevented NP cell apoptosis but did not affect anti-oxidative enzyme expression. Taken together, p-eIF2α/ATF4/Ihh signaling involves the ROS level and apoptosis in NP cells, the pharmacological disruption of which may provide promising methods in preventing IDD.

ADAMTS13 Regulates Neutrophil Recruitment in a Mouse Model of Invasive Pulmonary Aspergillosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4109-4109
Author(s):  
Markus Radsak ◽  
Steve Prüfer ◽  
Katharina Ebner ◽  
Michael Weber ◽  
Sebastian Reuter ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Mouse Model ◽  
Aspergillus Fumigatus ◽  
Fungal Infections ◽  
Invasive Pulmonary Aspergillosis ◽  
Polymorphonuclear Neutrophils ◽  
Formyl Peptide Receptor ◽  
Wild Type ◽  
Pulmonary Aspergillosis

Abstract Von Willebrand factor (VWF) is secreted as an acute phase protein during inflammation. The main mechanism regulating the size and prothrombotic activity of VWF is the specific proteolytic activity of ADAMTS-13. To determine the relevance of this regulatory pathway for the innate inflammatory response by polymorphonuclear neutrophils (PMN), we employed a mouse model of invasive pulmonary aspergillosis (IPA) where PMN functionality is crucial for fungal clearance and survival. IPA was induced by intratracheal application of Aspergillus fumigatus conidia in wild-type (129/Sv/Pas) or Adamts13 deficient (Adamts13-/-) mice. After PMN depletion using a anti-Gr-1 specific antibody, all mice infected with Aspergillus fumigatus conidia developed neutropenia and succumbed due to lethal IPA. In contrast, all undepleted wild-type mice survived the infection. Interestingly, Aspergillus fumigatus infection in Adamts13-/- mice was lethal in 20% of the animals displaying a more severe course of IPA, as indicated by an increased fungal burden in lung homogenates along with increased levels of albumin and the inflammatory mediators IL-1β, IL-6, TNF-α, KC and MCP-1 in the bronchio-alveolar lavage fluid (BALF) compared to wild-type controls. Beyond this, we observed a decreased number of PMN in BALF of infected Adamts13-/- mice compared to wild-type mice. Lung histology sections demonstrated a more pronounced perivascular leukocyte infiltration in further support of a dysregulated inflammatory response in Adamts13-/- mice. Importantly, we observed no general defect in the activation of neutrophil effector functions as demonstrated by the normal induction of the oxidative burst, phagocytosis, degranulation, L-selectin shedding and apoptosis in response to formyl-peptide receptor agonists or exposure to Aspergillus fumigatus conidia or hyphae in vitro. Therefore, we conclude that the proteolytic regulation of VWF by ADAMTS-13 in an important mechanism to control PMN recruitment in the regulation of the innate inflammatory response in invasive fungal infections. Disclosures Radsak: Celgene: Research Funding.

scholarly journals Lipid Peroxidation Modification of Protein Generates Nϵ-(4-Oxononanoyl)lysine as a Pro-inflammatory Ligand

2011 ◽  
Vol 286 (22) ◽  
pp. 19943-19957 ◽  
Author(s):  
Takahiro Shibata ◽  
Yuuki Shimozu ◽  
Chika Wakita ◽  
Noriyuki Shibata ◽  
Makio Kobayashi ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Vascular Endothelial Cells ◽  
Oxidized Ldl ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Oxidative Modification ◽  
Dependent Manner ◽  
Monocyte Chemoattractant Protein 1

4-Oxo-2(E)-nonenal (ONE), a peroxidation product of ω-6 polyunsaturated fatty acids, covalently reacts with lysine residues to generate a 4-ketoamide-type ONE-lysine adduct, Nϵ-(4-oxononanoyl)lysine (ONL). Using an ONL-coupled protein as the immunogen, we raised the monoclonal antibody (mAb) 9K3 directed to the ONL and conclusively demonstrated that the ONL was produced during the oxidative modification of a low density lipoprotein (LDL) in vitro. In addition, we observed that the ONL was present in atherosclerotic lesions, in which an intense immunoreactivity was mainly localized in the vascular endothelial cells and macrophage- and vascular smooth muscle cell-derived foam cells. Using liquid chromatography with on-line electrospray ionization tandem mass spectrometry, we also established a highly sensitive method for quantification of the ONL and confirmed that the ONL was indeed formed during the lipid peroxidation-mediated modification of protein in vitro and in vivo. To evaluate the biological implications for ONL formation, we examined the recognition of ONL by the scavenger receptor lectin-like oxidized LDL receptor-1 (LOX-1). Using CHO cells stably expressing LOX-1, we evaluated the ability of ONL to compete with the acetylated LDL and found that both the ONE-modified and ONL-coupled proteins inhibited the binding and uptake of the modified LDL. In addition, we demonstrated that the ONL-coupled protein was incorporated into differentiated THP-1 cells via LOX-1. Finally, we examined the effect of ONL on the expression of the inflammation-associated gene in THP-1 and observed that the ONL-coupled proteins significantly induced the expression of atherogenesis-related genes, such as the monocyte chemoattractant protein-1 and tumor necrosis factor-α, in a LOX-1-dependent manner. Thus, ONL was identified to be a potential endogenous ligand for LOX-1.

Wnt5a contributes to dectin-1 and LOX-1 induced host inflammatory response signature in Aspergillus fumigatus keratitis

2018 ◽  
Vol 52 ◽  
pp. 103-111 ◽  
Author(s):  
Chengye Che ◽  
Cui Li ◽  
Jing Lin ◽  
Jie Zhang ◽  
Nan Jiang ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Aspergillus Fumigatus ◽  
Host Inflammatory Response

scholarly journals Absence of Respiratory Burst in X-linked Chronic Granulomatous Disease Mice Leads to Abnormalities in Both Host Defense and Inflammatory Response to Aspergillus fumigatus

1997 ◽  
Vol 185 (2) ◽  
pp. 207-218 ◽  
Author(s):  
David E. Morgenstern ◽  
Mary A.C. Gifford ◽  
Ling Lin Li ◽  
Claire M. Doerschuk ◽  
Mary C. Dinauer
Keyword(s):  
Inflammatory Response ◽  
Aspergillus Fumigatus ◽  
Chronic Granulomatous Disease ◽  
Alveolar Macrophages ◽  
Respiratory Burst ◽  
Pulmonary Inflammation ◽  
Clinical Manifestations ◽  
Granulomatous Disease ◽  
Wild Type

Mice with X-linked chronic granulomatous disease (CGD) generated by targeted disruption of the gp91phox subunit of the NADPH–oxidase complex (X-CGD mice) were examined for their response to respiratory challenge with Aspergillus fumigatus. This opportunistic fungal pathogen causes infection in CGD patients due to the deficient generation of neutrophil respiratory burst oxidants important for damaging A. fumigatus hyphae. Alveolar macrophages from X-CGD mice were found to kill A. fumigatus conidia in vitro as effectively as alveolar macrophages from wild-type mice. Pulmonary disease in X-CGD mice was observed after administration of doses ranging from 105 to 48 spores, none of which produced disease in wild-type mice. Higher doses produced a rapidly fatal bronchopneumonia in X-CGD mice, whereas progression of disease was slower at lower doses, with development of chronic inflammatory lesions. Marked differences were also observed in the response of X-CGD mice to the administration of sterilized Aspergillus hyphae into the lung. Within 24 hours of administration, X-CGD mice had significantly higher numbers of alveolar neutrophils and increased expression of the proinflammatory cytokines IL-1β and TNF-α relative to the responses seen in wild-type mice. By one week after administration, pulmonary inflammation was resolving in wild-type mice, whereas X-CGD mice developed chronic granulomatous lesions that persisted for at least six weeks. This is the first experimental evidence that chronic inflammation in CGD does not always result from persistent infection, and suggests that the clinical manifestations of this disorder reflect both impaired microbial killing as well as other abnormalities in the inflammatory response in the absence of a respiratory burst.

Exportin 7 (RanBP16) Plays An Essential Role In Terminal Erythroid Differentiation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3877-3877
Author(s):  
Shilpa Hattangadi ◽  
Karly Burke ◽  
Harvey Lodish
Keyword(s):  
Cellular Proliferation ◽  
Conflicts Of Interest ◽  
Fetal Liver ◽  
Chromatin Condensation ◽  
Erythroid Differentiation ◽  
Erythroid Cell ◽  
Activating Transcription Factor 4 ◽  
Activating Transcription Factor ◽  
Terminal Erythroid Differentiation

Abstract Abstract 3877 Members of the nuclear transport receptor family of importins and exportins regulate the passage of proteins between the nucleus and cytoplasm. Although evolutionarily conserved across several species, Exportin 7 (Xpo7 or RanBP16) and its cargo are not well understood. In our study, we find that Xpo7 is highly erythroid-specific, as all other exportins are downregulated during terminal erythroid differentiation, a process including the induction of a highly specialized erythroid expression program, a set number of 3–5 terminal cell divisions, and chromatin condensation and eventual enucleation. Xpo7, in contrast, is highly induced during terminal erythropoiesis. Using retroviral shRNA knockdown of Xpo7 in in vitro fetal liver erythroid cell cultures, we demonstrate that exportin 7 is necessary for normal cellular proliferation and terminal erythroid differentiation, specifically for normal enucleation. Through microarray and biocomputational analysis of mRNA isolated from the knockdown cultures, we have found that the promoters of genes that are dysregulated after Xpo7 knockdown are enriched for binding sites for the activating transcription factor 4 (ATF4). Given that the erythroid phenotype of the ATF4 knockout mouse is very similar to the specific erythroid defects we observe in our in vitro knockdown analysis, our data suggests that either ATF4 or its binding protein may be Xpo7's cargo during terminal erythroid differentiation. Ongoing studies aimed at confirming this mechanism, the interaction between ATF4 and Xpo7, and the role and cargo of Xpo7 in terminal erythroid differentiation, are underway. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document