Treponema pallidum (syphilis) antigen TpF1 induces activation of macrophages and accelerates P2X7R-induced NLRP3-dependent release of IL-1β

2021 ◽  
Vol 21 ◽  
Author(s):  
Dong-Ping Lu ◽  
Jie Jia ◽  
Shao-Feng Wei ◽  
Wei-Lian Zhang ◽  
Rui Liang ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Clinical Symptoms ◽  
Treponema Pallidum ◽  
Pathological Process ◽  
Macrophage Phenotype ◽  
M1 Macrophage ◽  
Oligomeric Protein ◽  
Family Protein ◽  
Underlying Mechanisms

Background: Syphilis is a chronic infectious disease caused by Treponema pallidum (Tp) infection, which causes local inflammation in the host. TpF1 is an oligomeric protein expressed by the Tp-infected host that can induce the host immune response. There are few studies regarding the role of TpF1 in macrophage activation and the subsequent release of cytokines. Objective: To elucidate the effects of TpF1 on the pathological process of Syphilis. In addition, we explored how purinergic 2X7 (P2X7R) induced NOD-like receptor family protein 3 (NLRP3) -dependent release of interleukin-1β (IL-1β) and the underlying mechanisms. Methods: We explored the influence of TpF1 on cytokine release by macrophages using qRT-PCR and ELISA. The specific phenotype of activated macrophages was determined by flow cytometry. Results: TpF1 was able to activate macrophages and induce the M1 macrophage phenotype. Moreover, TpF1 activated the NLRP3 inflammasome in macrophages, which was mediated by P2X7R. Conclusions: The Tp-induced protein TpF1 is able to induce macrophage activation and P2X7R-induced NLRP3-dependent release of IL-1β. Our findings provide a theoretical basis for clarifying the clinical symptoms and pathogenesis of syphilis.

scholarly journals An antiinflammatory role for IKKβ through the inhibition of “classical” macrophage activation

2008 ◽  
Vol 205 (6) ◽  
pp. 1269-1276 ◽  
Author(s):  
Carol Ho Yan Fong ◽  
Magali Bebien ◽  
Arnaud Didierlaurent ◽  
Ruth Nebauer ◽  
Tracy Hussell ◽  
...  
Keyword(s):  
Mhc Class Ii ◽  
Macrophage Activation ◽  
Group B Streptococcus ◽  
Nuclear Factor Κb ◽  
Class Ii ◽  
Chronic Inflammatory Disease ◽  
Airway Epithelial Cells ◽  
Macrophage Phenotype ◽  
Iκb Kinase ◽  
M1 Macrophage

The nuclear factor κB (NF-κB) pathway plays a central role in inflammation and immunity. In response to proinflammatory cytokines and pathogen-associated molecular patterns, NF-κB activation is controlled by IκB kinase (IKK)β. Using Cre/lox-mediated gene targeting of IKKβ, we have uncovered a tissue-specific role for IKKβ during infection with group B streptococcus. Although deletion of IKKβ in airway epithelial cells had the predicted effect of inhibiting inflammation and reducing innate immunity, deletion of IKKβ in the myeloid lineage unexpectedly conferred resistance to infection that was associated with increased expression of interleukin (IL)-12, inducible nitric oxide synthase (NOS2), and major histocompatibility complex (MHC) class II by macrophages. We also describe a previously unknown role for IKKβ in the inhibition of signal transducer and activator of transcription (Stat)1 signaling in macrophages, which is critical for IL-12, NOS2, and MHC class II expression. These studies suggest that IKKβ inhibits the “classically” activated or M1 macrophage phenotype during infection through negative cross talk with the Stat1 pathway. This may represent a mechanism to prevent the over-exuberant activation of macrophages during infection and contribute to the resolution of inflammation. This establishes a new role for IKKβ in the regulation of macrophage activation with important implications in chronic inflammatory disease, infection, and cancer.

scholarly journals Context-enriched interactome powered by proteomics helps the identification of novel regulators of macrophage activation

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Arda Halu ◽  
Jian-Guo Wang ◽  
Hiroshi Iwata ◽  
Alexander Mojcher ◽  
Ana Luisa Abib ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
The Novel ◽  
Macrophage Phenotype ◽  
Loss Of Function ◽  
Prioritization Method ◽  
Network Proximity ◽  
Network Approaches ◽  
Inflammatory Macrophage

The role of pro-inflammatory macrophage activation in cardiovascular disease (CVD) is a complex one amenable to network approaches. While an indispensible tool for elucidating the molecular underpinnings of complex diseases including CVD, the interactome is limited in its utility as it is not specific to any cell type, experimental condition or disease state. We introduced context-specificity to the interactome by combining it with co-abundance networks derived from unbiased proteomics measurements from activated macrophage-like cells. Each macrophage phenotype contributed to certain regions of the interactome. Using a network proximity-based prioritization method on the combined network, we predicted potential regulators of macrophage activation. Prediction performance significantly increased with the addition of co-abundance edges, and the prioritized candidates captured inflammation, immunity and CVD signatures. Integrating the novel network topology with transcriptomics and proteomics revealed top candidate drivers of inflammation. In vitro loss-of-function experiments demonstrated the regulatory role of these proteins in pro-inflammatory signaling.

Abstract 18687: PARP9 and PARP14 are Novel Regulators of Macrophage Activation

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Hiroshi Iwata ◽  
Hideo Yoshida ◽  
Piero Ricchiuto ◽  
Takuya Hara ◽  
Iwao Yamada ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
High Resolution Mass Spectrometry ◽  
Macrophage Phenotype ◽  
Adp Ribosylation ◽  
Macrophage Activity ◽  
Arginase 1 ◽  
Anti Inflammatory ◽  
Unstable Plaques ◽  
Underlying Mechanisms

Background: Pro-inflammatory “M1” macrophages may promote atherogenesis, while “M2” macrophages may favor an anti-inflammatory milieu. Our global proteomics of M1 and M2 cells identified ADP-ribosylation enzymes PARP9 and PARP14 as novel regulators of macrophage activation. The present study has examined the underlying mechanisms and explored in vivo evidence for their role in vascular disease. Methods and Results: IFN gamma (M1) stimulation induced and IL-4 (M2) decreased PARP9 and PARP14 in mouse and human macrophages. siRNA silencing of PARP14 enhanced expression of M1 genes (e.g. TNFα, iNOS) and activation (phosphorylation) of pro-inflammatory STAT1 while suppressing M2 markers (e.g., Arginase 1) and anti-inflammatory STAT6. Conversely, PARP9 silencing suppressed M1 polarization and STAT1 activation. These results suggest that PARP14 inhibits and PARP9 promotes a pro-inflammatory macrophage phenotype. Co-immunoprecipitation indicated that PARP14 and PARP9 physically interact. ADP-ribosylation assays revealed that PARP9 impairs PARP14-induced ribosylation (Figure A). Targeted proteomics via high-resolution mass spectrometry demonstrated that PARP14 ADP-ribosylates at least two sites in STAT1α, which PARP9 suppressed. Mechanically injured arteries of Parp14-/- mice had accelerated lesion formation and macrophage accumulation. Peritoneal and plaque macrophages of PARP14-/- mice showed increased STAT1 phosphorylation, decreased STAT6 phosphorylation, enhanced M1 gene expression, and reduced M2 responses (Figure B, laser capture microdissection). More macrophages[[Unable to Display Character: &#61472;]]were immunoreactive for PARP9 in human “unstable” plaques than in “stable” plaques (64.6±16.2% vs. 30.8±12.3%, p<0.01, n=5). Conclusions: PARP14 and PARP9 reciprocally regulate the mechanisms of macrophage activation, offering the potential for new therapies for cardiovascular diseases and other conditions, in which macrophage activity impacts outcomes.

scholarly journals Depletion of microRNA-451 in response to allergen exposure accentuates asthmatic inflammation by regulating Sirtuin2

2020 ◽  
Vol 318 (5) ◽  
pp. L921-L930
Author(s):  
Sangwoon Chung ◽  
Yong Gyu Lee ◽  
Manjula Karpurapu ◽  
Joshua A. Englert ◽  
Megan N. Ballinger ◽  
...  
Keyword(s):  
Gene Expression ◽  
Airway Inflammation ◽  
Macrophage Activation ◽  
Airway Remodeling ◽  
Oxidant Stress ◽  
Allergic Inflammation ◽  
Allergic Airway Inflammation ◽  
Health Concern ◽  
Macrophage Phenotype

The incidence of asthma has increased from 5.5% to near 8% of the population, which is a major health concern. The hallmarks of asthma include eosinophilic airway inflammation that is associated with chronic airway remodeling. Allergic airway inflammation is characterized by a complex interplay of resident and inflammatory cells. MicroRNAs (miRNAs) are small noncoding RNAs that function as posttranscriptional modulators of gene expression. However, the role of miRNAs, specifically miR-451, in the regulation of allergic airway inflammation is unexplored. Our previous findings showed that oxidant stress regulates miR-451 gene expression in macrophages during an inflammatory process. In this paper, we examined the role of miR-451 in regulating macrophage phenotype using an experimental poly-allergenic murine model of allergic airway inflammation. We found that miR-451 contributes to the allergic induction of CCL17 in the lung and plays a key role in proasthmatic macrophage activation. Remarkably, administration of a Sirtuin 2 (Sirt2) inhibitor diminished alternate macrophage activation and markedly abrogated triple-allergen [dust mite, ragweed, Aspergillus fumigatus (DRA)]-induced lung inflammation. These data demonstrate a role for miR-451 in modulating allergic inflammation by influencing allergen-mediated macrophages phenotype.

scholarly journals The role of endoscopic ultrasound investigation in the diagnosis of submucosal neoplasms of the stomach and duodenum (literature review and our clinical observations)

2021 ◽  
Vol 55 (4) ◽  
pp. 270-279
Author(s):  
Yu.M. Stepanov ◽  
N.V. Prolom ◽  
I.S. Konenko ◽  
S.O. Tarabarov ◽  
N.P. Dementii ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Pathological Process ◽  
Endoscopic Examination ◽  
Malignant Neoplasms ◽  
Medical Sciences ◽  
Regional Lymph Nodes ◽  
Submucosal Tumors ◽  
Clinical Observations ◽  
Submucosal Lesions

Submucosal neoplasms of the stomach and duodenum include a group of diseases with different etiology, clinical symptoms, diagnosis and management. Conventional gastroduodenoscopy helps detect submucosal formations in 0.36–4 % of cases, while the stomach is the most common site of submucosal lesions (up to 60 %). Endoscopy and ultrasound endoscopic examination are important tools for the diagnosis of submucosal tumors of the esophagus, stomach, duodenum, both benign (polyps, submucosal formations, extraorganic compression, cysts) and malignant neoplasms of the gastrointestinal tract, especially small and accidentally detected. It is important not only to diagnose the tumor, but also to determine from which layers it comes, what level germinates, whether there is damage to regional lymph nodes. Only endoscopic ultrasonography (EUS) can answer these questions. EUS combines the capabilities of two studies: endoscopic and ultrasound, which significantly increased the informativeness of endoscopic examination, as it was possible to determine the site of the pathological process and the degree of intramural invasion, and also made it possible to carry out the differential diagnosis of submucosal tumors and pathological processes in organs adjacent to the esophagus, stomach, duodenum. The article presents examinations of patients with submucous formations of the stomach and duodenum at the Institute of Gastroenterology of the National Academy of Medical Sciences of Ukraine. With the help of EUS, the diagnosis was confirmed in one patient, and in another one, the submucosal neoplasms was excluded.

scholarly journals P0530A NOVEL LNCRNA(LRAN9884) PROMOTES AKI VIA MAINTAINING MINCLE-DEPENDENT M1 MACROPHAGE PHENOTYPE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Yingying Zhang ◽  
Chen Yu
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Underlying Mechanism ◽  
M2 Macrophage ◽  
Macrophage Phenotype ◽  
Rt Pcr ◽  
M1 Macrophage ◽  
Tnf Α ◽  
Inflammatory Macrophage

Abstract Background and Aims Macrophages are key inflammatory cells and play a critical role in renal inflammation in acute kidney injury (AKI). M1 inflammatory macrophage and M2 anti-inflammatory macrophage act reverse role. Phenotype of macrophages is highly flexible and can be changed over time. However, the underlying mechanism of M1 and M2 macrophage phenotype switching during AKI is still largely unclear. In our previous study, we identified a novel lncRNA (LRNA9884) might contribute to inflammation according to modifying macrophages. The present study was designed to uncover the pathogenic role and the underlying mechanism of LRNA9884 in cisplatin-induced AKI. Method Expression level and pattern of LRNA9884 were examined in cisplatin-induced AKI mice. The regulatory mechanisms of LRNA9884 was investigated in cultured bone marrow–derived macrophages (BMDMs) in vitro by silencing or overexpressing of LRNA9884. Flow Cytometer, fluorescence in situ hybridization (FISH) and other multiple molecular biological techniques were applied to figure out the role of LRNA9884 under acute kidney injury. Results LRNA9884 was significantly upregulated in the kidney of cisplatin-induced mice and was associated with the progression of the renal inflammation by using RT-PCR and ISH assay. FISH assay with immunofluorescence co-staining detected that LRNA9884 was largely expressed in the nucleus of macrophage in cisplatin-induced mice kidney compared with the sham group at day 1 after AKI injury. LRNA9884 was remarkedly induced by TNF-α (10ng/ml) in BMDMs as time- and dose- dependent. Western blot and RT-PCR showed that silencing of LRNA9884 effectively inhibited upregulated of macrophage-inducible C-type lectin (Mincle) and iNOS induced by TNF-α. More importantly, we identified that LRNA9884 maintained M1 macrophages phenotype by triggering mincle production at transcriptional level as evidenced by ChIP assay. Conclusion LRNA9884 is a mincle-dependent lncRNA that highly-expressed in macrophages under AKI development. Targeting of LRNA9884 effectively blocked the inflammatory response via promoting the transition M1 macrophage to M2 macrophage phenotype. This study will shed new lights on the understanding of pathological role of novel LRNA9884 in AKI.

Neutrophil-Derived Exosomes Induce M1 Macrophage Polarization and Prime Macrophage Pyroptosis via miR-30d-5p in Sepsis

2021 ◽  
Author(s):  
Yang Jiao ◽  
Ti Zhang ◽  
Chengmi Zhang ◽  
Haiying Ji ◽  
Xingyu Tong ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Macrophage Polarization ◽  
Cecal Ligation ◽  
Polymorphonuclear Neutrophils ◽  
Raw264.7 Macrophages ◽  
M1 Macrophage ◽  
Tnf Α

Abstract Background: Polymorphonuclear neutrophils (PMNs) have been demonstrated to play a role in proinflammatory M1 activation and macrophage (Mϕ) pyroptosis in sepsis. Accumulating evidence suggests PMN-derived exosomes as a new subcellular entity acting as a fundamental link between PMN-driven inflammation and tissue damage. However, the role of PMN-derived exosomes in sepsis remains unclear. This study aimed to determine whether PMN-derived exosomes play a role in proinflammatory M1 activation and Mϕ pyroptosis in sepsis and explore the potential mechanisms involved. Methods: Exosomes were isolated from the supernatant of PMNs activated with phosphate buffered saline (PBS) or tumor necrosis factor (TNF)-α, cocultured with Raw264.7 macrophages or BMDMs, and then assayed for macrophage polarization and pyroptosis. To examine the role of exosomes in vivo, PMN-derived exosomes were administered to mice, and then examined for lung inflammation. Results: After activated by TNF-α, PMNs released exosomes (TNF-Exo) to promote M1 macrophage activation both in vivo and in vitro. In addition, TNF-Exo primed macrophages for pyroptosis by upregulating NLRP3 inflammasome expression through NF-κB signaling pathway. Mechanistic studies demonstrated that miR-30d-5p mediated the function of TNF-Exo by targeting SOCS-1 and SIRT1 in macrophages. Furthermore, treatment of miR-30d-5p inhibitors in vivo significantly decreased cecal ligation and puncture (CLP) or TNF-Exo-induced M1 macrophage activation and macrophage death in the lung. Lung injury was also alleviated by miR-30d-5p inhibitors.Conclusions: In this study, we identified a novel mechanism of PMN-Mϕ interaction in sepsis, demonstrating that exosomal miR-30d-5p from PMNs induced M1 macrophage polarization and primed Mϕ for pyroptosis by activating NF-κB signaling. These findings suggest a previously unidentified role of neutrophil-derived exosomes in sepsis and may lead to new therapeutic approaches.

scholarly journals PAK1 Silencing Attenuated Proinflammatory Macrophage Activation and Foam Cell Formation by Increasing PPARγ Expression

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Wen-Lin Cheng ◽  
Quan Zhang ◽  
Bo Li ◽  
Jian-Lei Cao ◽  
Lin Jiao ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Foam Cell ◽  
Macrophage Polarization ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
M2 Macrophage ◽  
Macrophage Phenotype ◽  
Loss Of Function ◽  
M1 Macrophage ◽  
Pparγ Expression

Macrophage polarization in response to environmental cues has emerged as an important event in the development of atherosclerosis. Compelling evidences suggest that P21-activated kinases 1 (PAK1) is involved in a wide variety of diseases. However, the potential role and mechanism of PAK1 in regulation of macrophage polarization remains to be elucidated. Here, we observed that PAK1 showed a dramatically increased expression in M1 macrophages but decreased expression in M2 macrophages by using a well-established in vitro model to study heterogeneity of macrophage polarization. Adenovirus-mediated loss-of-function approach demonstrated that PAK1 silencing induced an M2 macrophage phenotype-associated gene profiles but repressed the phenotypic markers related to M1 macrophage polarization. Additionally, dramatically decreased foam cell formation was found in PAK1 silencing-induced M2 macrophage activation which was accompanied with alternation of marker account for cholesterol efflux or influx from macrophage foam cells. Moderate results in lipid metabolism and foam cell formation were found in M1 macrophage activation mediated by AdshPAK1. Importantly, we presented mechanistic evidence that PAK1 knockdown promoted the expression of PPARγ, and the effect of macrophage activation regulated by PAK1 silencing was largely reversed when a PPARγ antagonist was utilized. Collectively, these findings reveal that PAK1 is an independent effector of macrophage polarization at least partially attributed to regulation of PPARγ expression, which suggested PAK1-PPARγ axis as a novel therapeutic strategy in atherosclerosis management.

Response Interference as a Mechanism Underlying Implicit Measures

2008 ◽  
Vol 24 (4) ◽  
pp. 218-225 ◽  
Author(s):  
Bertram Gawronski ◽  
Roland Deutsch ◽  
Etienne P. LeBel ◽  
Kurt R. Peters
Keyword(s):  
Task Performance ◽  
Psychological Research ◽  
Implicit Measures ◽  
Mediation Model ◽  
Response Interference ◽  
Relevant Evidence ◽  
Moderated Mediation Model ◽  
Stimulus Features ◽  
Underlying Mechanisms

Over the last decade, implicit measures of mental associations (e.g., Implicit Association Test, sequential priming) have become increasingly popular in many areas of psychological research. Even though successful applications provide preliminary support for the validity of these measures, their underlying mechanisms are still controversial. The present article addresses the role of a particular mechanism that is hypothesized to mediate the influence of activated associations on task performance in many implicit measures: response interference (RI). Based on a review of relevant evidence, we argue that RI effects in implicit measures depend on participants’ attention to association-relevant stimulus features, which in turn can influence the reliability and the construct validity of these measures. Drawing on a moderated-mediation model (MMM) of task performance in RI paradigms, we provide several suggestions on how to address these problems in research using implicit measures.

The More You Say, the Less They Hear

2015 ◽  
Vol 27 (4) ◽  
pp. 159-169 ◽  
Author(s):  
Elsbeth D. Asbeek Brusse ◽  
Marieke L. Fransen ◽  
Edith G. Smit
Keyword(s):  
Hearing Protection ◽  
Entertainment Education ◽  
Mediating Role ◽  
Attitude Measures ◽  
Underlying Mechanisms

Abstract. This study examined the effects of disclosure messages in entertainment-education (E-E) on attitudes toward hearing protection and attitude toward the source. In addition, the (mediating) role of the underlying mechanisms (i.e., transportation, identification, and counterarguing) was studied. In an experiment (N = 336), three different disclosure messages were compared with a no-disclosure condition. The results show that more explicit disclosure messages negatively affect transportation and identification and stimulate the generation of counterarguments. In addition, the more explicit disclosure messages affect both attitude measures via two of these processes (i.e., transportation and counterarguing). Less explicit disclosure messages do not have this effect. Implications of the findings are discussed.

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