scholarly journals Whole-BodyIn VivoMonitoring of Inflammatory Diseases Exploiting Human Interleukin 6-Luciferase Transgenic Mice

2015 ◽  
Vol 35 (20) ◽  
pp. 3590-3601 ◽  
Author(s):  
Makiko Hayashi ◽  
Jun Takai ◽  
Lei Yu ◽  
Hozumi Motohashi ◽  
Takashi Moriguchi ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Genetic Model ◽  
Imaging System ◽  
Inflammatory Diseases ◽  
Chronic Inflammatory Disease ◽  
Whole Body ◽  
Disease Models ◽  
Bac Clone ◽  
Inflammatory Status

Chronic inflammation underlies the pathological progression of various diseases, and thus many efforts have been made to quantitatively evaluate the inflammatory status of the diseases. In this study, we generated a highly sensitive inflammation-monitoring mouse system using a bacterial artificial chromosome (BAC) clone containing extended flanking sequences of the human interleukin 6 gene (hIL6) locus, in which the luciferase (Luc) reporter gene is integrated (hIL6-BAC-Luc). We successfully monitored lipopolysaccharide-induced systemic inflammation in various tissues of thehIL6-BAC-Lucmice using anin vivobioluminescence imaging system. When two chronic inflammatory disease models, i.e., a genetic model of atopic dermatitis and a model of experimental autoimmune encephalomyelitis (EAE), were applied to thehIL6-BAC-Lucmice, luciferase bioluminescence was specifically detected in the atopic skin lesion and central nervous system, respectively. Moreover, the Luc activities correlated well with the disease severity. Nrf2 is a master transcription factor that regulates antioxidative and detoxification enzyme genes. Upon EAE induction, the Nrf2-deficient mice crossed with thehIL6-BAC-Lucmice exhibited enhanced neurological symptoms concomitantly with robust luciferase luminescence in the neuronal tissue. Thus, whole-bodyin vivomonitoring using thehIL6-BAC-Luctransgenic system (WIM-6 system) provides a new and powerful diagnostic tool for real-timein vivomonitoring of inflammatory status in multiple different disease models.

scholarly journals Lipid, fatty acid, carnitine- and choline derivative profiles in rheumatoid arthritis outpatients with different degrees of periodontal inflammation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kathrin Beyer ◽  
Stein Atle Lie ◽  
Bodil Bjørndal ◽  
Rolf K. Berge ◽  
Asbjørn Svardal ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Fatty Acid ◽  
Mitochondrial Dysfunction ◽  
Inflammatory Diseases ◽  
Whole Body ◽  
Cross Sectional ◽  
Chronic Inflammatory Diseases ◽  
Periodontal Inflammation ◽  
Inflammatory Status ◽  
Lipid Fatty Acid

AbstractRheumatoid arthritis (RA) and periodontitis are chronic inflammatory diseases with several pathogenic pathways in common. Evidence supports an association between the diseases, but the exact underlying mechanisms behind the connection are still under investigation. Lipid, fatty acid (FA) and metabolic profile alterations have been associated with several chronic inflammatory diseases, including RA and periodontitis. Mitochondria have a central role in regulating cellular bioenergetic and whole-body metabolic homeostasis, and mitochondrial dysfunction has been proposed as a possible link between the two disorders. The aim of this cross-sectional study was to explore whole-blood FA, serum lipid composition, and carnitine- and choline derivatives in 78 RA outpatients with different degrees of periodontal inflammation. The main findings were alterations in lipid, FA, and carnitine- and choline derivative profiles. More specifically, higher total FA and total cholesterol concentrations were found in active RA. Elevated phospholipid concentrations with concomitant lower choline, elevated medium-chain acylcarnitines (MC-AC), and decreased ratios of MC-AC and long-chain (LC)-AC were associated with prednisolone medication. This may indicate an altered mitochondrial function in relation to the increased inflammatory status in RA disease. Our findings may support the need for interdisciplinary collaboration within the field of medicine and dentistry in patient stratification to improve personalized treatment. Longitudinal studies should be conducted to further assess the potential impact of mitochondrial dysfunction on RA and periodontitis.

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.

Abstract 14935: Targeted Optical Molecular Imaging of Atheroma Calcification Using Novel Aldendronate-based Probe

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Dong Oh Kang ◽  
Yong Geun Lim ◽  
Joon Woo Song ◽  
Ye Hee Park ◽  
Hyun Jung Kim ◽  
...  
Keyword(s):  
Molecular Imaging ◽  
High Resolution ◽  
Murine Model ◽  
Calcium Binding ◽  
Laser Scanning ◽  
Near Infrared ◽  
Imaging System ◽  
Whole Body ◽  
Imaging Results

Background/Objectives: Vascular spotty calcification is an actively regulated biological process resulting in plaque vulnerability. We investigated the feasibility of a novel alendronate-based near-infrared fluorescence (NIRF)-emitting probe to specifically target atherosclerotic calcification in a murine model in vivo using our customized high-resolution multichannel intravital molecular imaging system (IVFM). Methods/Results: We have fabricated a calcium-binding NIRF probe by chemically coupling alendronate, a specific targeting ligand, and NIRF-emitting Cy5.5 to the ends of azide-PEG-NHS ester (Al-Cy5.5). Prepared Al-Cy5.5 has high affinity for calcium phosphate-containing bone minerals. In vitro, Al-Cy5.5 specifically binds to RANKL-induced osteogenic-macrophages as compared to macrophages (p<0.01). On whole body fluorescence imaging to assess time-dependent excretion, NIRF signals remained visible up to 48 hrs. Then, in mice with calcified plaque induced by a combination diet of high-cholesterol and warfarin, Al-Cy5.5 (2.5 mg/kg) was intravenously injected. 48 hrs after administration, murine calcified atheroma was assessed using a customized high-resolution multichannel IVFM, which demonstrated highly enhanced NIRF signals in vivo in the calcified areas of murine carotid plaques (p<0.01, Figure). Ex vivo laser scanning fluorescence microscopic and immune-histological findings from the corresponding sister sections well corroborated the in vivo imaging results, which demonstrated the co-localization of NIRF signals with plaque calcifications (von-Kossa stain). Conclusions: Our novel calcification targeted probe, Al-Cy5.5, was able to selectively target atheroma calcification in vivo in a murine model as assessed by optical IVFM. This novel targetable strategy is expected to provide a promising theranostic basis for calcified high-risk plaques by integration with multimodal customized catheter imaging system.

scholarly journals Mast cells counteract regulatory T-cell suppression through interleukin-6 and OX40/OX40L axis toward Th17-cell differentiation

Blood ◽  
2009 ◽  
Vol 114 (13) ◽  
pp. 2639-2648 ◽  
Author(s):  
Silvia Piconese ◽  
Giorgia Gri ◽  
Claudio Tripodo ◽  
Silvia Musio ◽  
Andrea Gorzanelli ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mast Cells ◽  
Interleukin 6 ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Effector T Cells ◽  
Treg Suppression

Abstract The development of inflammatory diseases implies inactivation of regulatory T (Treg) cells through mechanisms that still are largely unknown. Here we showed that mast cells (MCs), an early source of inflammatory mediators, are able to counteract Treg inhibition over effector T cells. To gain insight into the molecules involved in their interplay, we set up an in vitro system in which all 3 cellular components were put in contact. Reversal of Treg suppression required T cell–derived interleukin-6 (IL-6) and the OX40/OX40L axis. In the presence of activated MCs, concomitant abundance of IL-6 and paucity of Th1/Th2 cytokines skewed Tregs and effector T cells into IL-17–producing T cells (Th17). In vivo analysis of lymph nodes hosting T-cell priming in experimental autoimmune encephalomyelitis revealed activated MCs, Tregs, and Th17 cells displaying tight spatial interactions, further supporting the occurrence of an MC-mediated inhibition of Treg suppression in the establishment of Th17-mediated inflammatory responses.

scholarly journals Measurement of whole body interleukin-6 (IL-6) production: prediction of the efficacy of anti-IL-6 treatments

Blood ◽  
1995 ◽  
Vol 86 (8) ◽  
pp. 3123-3131 ◽  
Author(s):  
ZY Lu ◽  
H Brailly ◽  
J Wijdenes ◽  
R Bataille ◽  
JF Rossi ◽  
...  
Keyword(s):  
Immune Complexes ◽  
Interleukin 6 ◽  
Acute Phase Protein ◽  
Whole Body ◽  
Tumor Proliferation ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Phase Protein ◽  
New Strategies

A major limitation on the therapeutic use of cytokine antagonists is that the amount of cytokine to be neutralized in vivo is not presently known. We previously reported that anti-interleukin-6 (IL-6) monoclonal antibody (MoAb) administered to a patient with multiple myeloma (MM) induced high amounts of IL-6 to circulate in the form of monomeric immune complexes. Based on this observation, the present study developed a new methodology to estimate daily IL-6 production in 13 patients with MM or renal cancer who received anti-IL-6 MoAb. Treatment was considered effective when the production of C-reactive protein (CRP) was inhibited. The production of this acute-phase protein by hepatocytes is dependent on the activation of IL-6 gp130 transducer. Inhibition of tumor proliferation was also evaluated in patients with MM. In 7 of 13 patients whose CRP production was completely inhibited (> 96%) and who showed some antitumoral effects, whole-body IL-6 production in vivo was less than 18 micrograms/d (median, 5.7 micrograms/d; range, 0.5 to 17.5 micrograms/d). In the other 6 patients, subtotal inhibition of CRP production and a lack of antitumoral response were associated with high IL-6 production (median, 180 micrograms/d; range, 18 to 358 micrograms/d). These in vivo observations were consistent with mathematical modeling that predicted that anti-IL-6 MoAb treatment would be efficient only in low IL-6 producers. These data indicate the difficulty of neutralizing IL-6 with a single anti-IL-6 MoAb in vivo and call for new strategies to avoid accumulation of IL-6 in the form of stable immune complexes.

scholarly journals Cigarette smoke inducesmiR-132in Th17 cells that enhance osteoclastogenesis in inflammatory arthritis

2020 ◽  
Vol 118 (1) ◽  
pp. e2017120118
Author(s):  
Paula B. Donate ◽  
Kalil Alves de Lima ◽  
Raphael S. Peres ◽  
Fausto Almeida ◽  
Sandra Y. Fukada ◽  
...  
Keyword(s):  
Cigarette Smoking ◽  
Inflammatory Arthritis ◽  
Th17 Cells ◽  
Inflammatory Diseases ◽  
Joint Destruction ◽  
Chronic Inflammatory Disease ◽  
Healthy Individuals ◽  
Aryl Hydrocarbon ◽  
The Impact

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint destruction and severe morbidity. Cigarette smoking (CS) can exacerbate the incidence and severity of RA. Although Th17 cells and the Aryl hydrocarbon receptor (AhR) have been implicated, the mechanism by which CS induces RA development remains unclear. Here, using transcriptomic analysis, we show thatmicroRNA-132is specifically induced in Th17 cells in the presence of either AhR agonist or CS-enriched medium.miRNA-132thus induced is packaged into extracellular vesicles produced by Th17 and acts as a proinflammatory mediator increasing osteoclastogenesis through the down-regulation of COX2. In vivo, articular knockdown ofmiR-132in murine arthritis models reduces the number of osteoclasts in the joints. Clinically, RA patients express higher levels ofmiR-132than do healthy individuals. This increase is further elevated by cigarette smoking. Together, these results reveal a hitherto unrecognized mechanism by which CS could exacerbate RA and further advance understanding of the impact of environmental factors on the pathogenesis of chronic inflammatory diseases.

scholarly journals IL-27Rα: A Novel Molecular Imaging Marker for Allograft Rejection

2020 ◽  
Vol 21 (4) ◽  
pp. 1315 ◽  
Author(s):  
Shanshan Zhao ◽  
Dai Shi ◽  
Chen Su ◽  
Wen Jiang ◽  
Chao Zhang ◽  
...  
Keyword(s):  
Molecular Imaging ◽  
Graft Rejection ◽  
Ex Vivo ◽  
Inflammatory Diseases ◽  
Whole Body ◽  
Specific Marker ◽  
Post Transplantation ◽  
Ex Vivo Biodistribution

Non-invasively monitoring allogeneic graft rejection with a specific marker is of great importance for prognosis of patients. Recently, data revealed that IL-27Rα was up-regulated in alloreactive CD4+ T cells and participated in inflammatory diseases. Here, we evaluated whether IL-27Rα could be used in monitoring allogeneic graft rejection both in vitro and in vivo. Allogeneic (C57BL/6 donor to BALB/c recipient) and syngeneic (BALB/c both as donor and recipient) skin grafted mouse models were established. The expression of IL-27Rα in grafts was detected. The radio-probe, 125I-anti-IL-27Rα mAb, was prepared. Dynamic whole-body phosphor-autoradiography, ex vivo biodistribution and immunofluorescence staining were performed. The results showed that the highest expression of IL-27Rα was detected in allogeneic grafts on day 10 post transplantation (top period of allorejection). 125I-anti-IL-27Rα mAb was successfully prepared with higher specificity and affinity. Whole-body phosphor-autoradiography showed higher radioactivity accumulation in allogeneic grafts than syngeneic grafts on day 10. The uptake of 125I-anti-IL-27Rα mAb in allogeneic grafts could be almost totally blocked by pre-injection with excess unlabeled anti-IL-27Rα mAb. Interestingly, we found that 125I-anti-IL-27Rα mAb accumulated in allogeneic grafts, along with weaker inflammation earlier on day 6. The high uptake of 125I-anti-IL-27Rα mAb was correlated with the higher infiltrated IL-27Rα positive cells (CD3+/CD68+) in allogeneic grafts. In conclusion, IL-27Rα may be a novel molecular imaging marker to predict allorejection.

Kinetics, Redistribution And Fate Of Indium-111-Labelled-Platelets In Patients With Aortic Aneurysms

1981 ◽  
Author(s):  
A duP Heyns ◽  
M G Lötter ◽  
P N Badenhorst ◽  
F de Kock ◽  
H Pieters ◽  
...  
Keyword(s):  
Imaging System ◽  
Reticuloendothelial System ◽  
Aortic Aneurysms ◽  
Whole Body ◽  
Computer Assisted ◽  
Scintillation Camera ◽  
Normal Limits ◽  
Geometrical Mean ◽  
Indium 111

Platelets of 7 patients with abdominal aortic aneurysms were labelled with In-lll-oxine prior to surgery. The platelets were reinjected with the patient positioned under a scintillation camera with a computer assisted imaging system. Images were acquisitioned daily, areas of interest selected with the computer, organ radioactivity- quantitated with a geometrical mean method and expressed as a percentage of whole body radioactivity. Platelet survival (PS) in the circulation was determined, and disappearance curves fitted to a gamma function “multiple hit” model.Mean PS was shorthened to 143,2 ± 47h (normal 232<17); the dissappearance curves were exponential in all but the two patients who had PS within normal limits. The surgically removed aneurysms were dissected and radioactivity of different layers measured. In-111-activity was confined to the superficial layers of the aneurysm.These techniques allow quantitative studies of the in vivo distribution of labelled platelets. Platelets are deposited in the aneurysms, this shortens PS, the disappearance curves become exponential, and the major sites of deposition of In-111-activity are in the liver and spleen. This indicates that although platelets are damaged and deposited in the aneurysm, the reticuloendothelial system remains a major site of platelet sequestration.

Abstract 9389: Thrombus Formation Processes are Dependent on Endothelial Injuries: Examined by in vivo Two-photon Molecular Imaging

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Satoshi Nishimura
Keyword(s):  
Imaging System ◽  
Thrombus Formation ◽  
Cellular Mechanisms ◽  
Cell Dynamics ◽  
Tlr4 Signaling ◽  
Two Photon Microscopy ◽  
Two Photon ◽  
Inflammatory Status ◽  
Thrombotic Diseases

Aim: The cellular mechanisms of thrombotic diseases associated with cardiovascular events remains unclear, largely because of an inability to visualize thrombus formation. Thus, we developed in vivo imaging technique based on single- and multi-photon microscopy and laser injuries technique to revealed the multicellular processes during thrombus development. Methods: We visualized the cell dynamics including single platelet behavior, and assessed dynamic cellular interplay in two thrombosis models using two photon microscopy to CAG-eGFP mice (Figure a, b). Results: First, we visualized that rapidly developing thrombi composed of discoid platelets without EC disruption was triggered by ROS induced by laser irradiation (Figure c). In this model, thrombus consisted by discoid platelet aggregations without leukocyte recruitment and not affected by Gr-1 antibody. The second model is, thrombus with EC disruption. High power laser induced EC erosion and extravasations of circulating leukocytes with thrombus development. Inflammatory cytokine, adhesion molecules dynamically control these two processes, and Gr-1 antibody significantly suppressed these steps. (Figure d) Leukocyte was immediately recruited into the subendothelial layers with bleeding and hemostatic reactions, and TLR4 signaling contributed to these steps. Pretreatmet of LPS or ischemic procedures markedly enhanced these steps. Thrombus included calcium activated cores and deformed platelets. Immigrated leukocyte also showed the increase of intracellular calcium. Summary: These results indicated that endothelial function, especially inflammatory status, determined the thrombotic reaction. Leukocyte also contributed with TLR4 signaling. In sum, using our imaging system can be a powerful tool to analyze thrombus formation and evaluate the therapeutic strategies.

scholarly journals Measurement of whole body interleukin-6 (IL-6) production: prediction of the efficacy of anti-IL-6 treatments

Blood ◽  
1995 ◽  
Vol 86 (8) ◽  
pp. 3123-3131 ◽  
Author(s):  
ZY Lu ◽  
H Brailly ◽  
J Wijdenes ◽  
R Bataille ◽  
JF Rossi ◽  
...  
Keyword(s):  
Immune Complexes ◽  
Interleukin 6 ◽  
Acute Phase Protein ◽  
Whole Body ◽  
Tumor Proliferation ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Phase Protein ◽  
New Strategies

Abstract A major limitation on the therapeutic use of cytokine antagonists is that the amount of cytokine to be neutralized in vivo is not presently known. We previously reported that anti-interleukin-6 (IL-6) monoclonal antibody (MoAb) administered to a patient with multiple myeloma (MM) induced high amounts of IL-6 to circulate in the form of monomeric immune complexes. Based on this observation, the present study developed a new methodology to estimate daily IL-6 production in 13 patients with MM or renal cancer who received anti-IL-6 MoAb. Treatment was considered effective when the production of C-reactive protein (CRP) was inhibited. The production of this acute-phase protein by hepatocytes is dependent on the activation of IL-6 gp130 transducer. Inhibition of tumor proliferation was also evaluated in patients with MM. In 7 of 13 patients whose CRP production was completely inhibited (> 96%) and who showed some antitumoral effects, whole-body IL-6 production in vivo was less than 18 micrograms/d (median, 5.7 micrograms/d; range, 0.5 to 17.5 micrograms/d). In the other 6 patients, subtotal inhibition of CRP production and a lack of antitumoral response were associated with high IL-6 production (median, 180 micrograms/d; range, 18 to 358 micrograms/d). These in vivo observations were consistent with mathematical modeling that predicted that anti-IL-6 MoAb treatment would be efficient only in low IL-6 producers. These data indicate the difficulty of neutralizing IL-6 with a single anti-IL-6 MoAb in vivo and call for new strategies to avoid accumulation of IL-6 in the form of stable immune complexes.

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