scholarly journals Neutrophil reverse migration from liver fuels neutrophilic inflammation to tissue injury in Nonalcoholic Steatohepatitis

2021 ◽  
Author(s):  
Maria Feliz-Norberto ◽  
Cassia Michael ◽  
Sofia de Oliveira
Keyword(s):  
Systemic Inflammation ◽  
Tissue Injury ◽  
Neutrophil Recruitment ◽  
Transgenic Zebrafish ◽  
Low Grade ◽  
Zebrafish Model ◽  
Nonalcoholic Fatty Liver ◽  
Neutrophilic Inflammation ◽  
Reverse Migration ◽  
Neutrophil Response

AbstractInflammation is a hallmark in the progression of nonalcoholic-fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). Patients with NAFLD are characterized by a chronic low-grade systemic metabolic inflammation (i.e., metainflammation), which contributes to exacerbated however dysfunctional immune response. Neutrophils play an important pathological role in NAFLD progression to NASH; however, how NASH and associated chronic systemic inflammation impact overall the neutrophil response to injury is completely unexplored. Here, we investigated how neutrophil response to tissue injury is altered by the presence of NASH. We used a diet-induced NASH zebrafish model combined with tailfin transection in transgenic zebrafish larvae to study neutrophilic inflammation. Live non-invasive confocal microscopy was used to investigate neutrophil recruitment to tailfin injury through time. Photoconvertion of neutrophils at the liver area followed by time-lapse microscopy was performed to evaluate migration of neutrophils from liver to tailfin injury. Metformin and Pentoxifylline were used to pharmacologically reduce NASH and liver inflammation. We found that larvae with NASH display systemic inflammation and increased myelopoiesis. NASH larvae display a dysfunctional and exacerbated neutrophil response to tailfin injury, characterized by increased neutrophil recruitment, and delayed resolution of inflammation. Interestingly, we showed that neutrophils undergo reverse migration from the NASH liver to the wounded tailfin area. Finally, pharmacological treatment of NASH with Pentoxifylline and Metformin significantly reduced systemic chronic inflammation and the exacerbated recruitment of neutrophils to tissue injury. Taken together, our findings suggest that NASH exacerbates neutrophilic inflammation probably via neutrophil priming at the liver, which can further undergo reverse migration and respond to secondary inflammatory triggers such as tissue injury. Reverse migration of primed neutrophils from the liver might be an important mechanism that fuels the exacerbated neutrophil response observed in NASH conditions and associated metainflammation contributing to poor prognosis and increasing death in patients with metabolic syndrome.

scholarly journals The CXCL12/CXCR4 signalling axis retains neutrophils at inflammatory sites in zebrafish

2019 ◽  
Author(s):  
Hannah M. Isles ◽  
Kimberly Herman ◽  
Anne L. Robertson ◽  
Catherine A. Loynes ◽  
Lynne R. Prince ◽  
...  
Keyword(s):  
Inflammatory Disease ◽  
Tissue Damage ◽  
Tissue Injury ◽  
Transgenic Zebrafish ◽  
Sequencing Data ◽  
Cxcr4 Antagonist ◽  
Reverse Migration ◽  
Zebrafish Larvae ◽  
Inflammation Resolution

AbstractThe inappropriate retention of neutrophils in the lung is a major driver of the excessive tissue damage characteristic of respiratory inflammatory diseases including COPD, ARDS and cystic fibrosis. The molecular programmes which orchestrate neutrophil recruitment to inflammatory sites through chemotactic guidance have been well studied. However, how neutrophil sensitivity to these cues is modulated during inflammation resolution is not understood. The identification of neutrophil reverse migration as a mechanism of inflammation resolution and the ability to modulate this therapeutically has identified a new target to treat inflammatory disease. Here we investigate the role of the CXCL12/CXCR4 signalling axis in modulating neutrophil retention at inflammatory sites. We used an in vivo tissue injury model to study inflammation using transgenic zebrafish larvae. Expression of cxcl12a and cxcr4b during the tissue damage response was assessed using in situ hybridisation and analysis of RNA sequencing data. CRISPR/Cas9 was used to knockdown cxcl12a and cxcr4b in zebrafish larvae. The CXCR4 antagonist AMD3100 was used to block the Cxcl12/Cxcr4 signalling axis pharmacologically. We identified that cxcr4b and cxcl12a are expressed at the wound site in zebrafish larvae during the inflammatory response. Following tail-fin transection, removal of neutrophils from inflammatory sites is significantly increased in cxcr4b and cxcl12a CRISPR knockdown larvae. Pharmacological inhibition of the Cxcl12/Cxcr4 signalling axis accelerates inflammation resolution, an effect caused by an increase in neutrophil reverse migration. The findings of this study suggest that CXCR4/CXCL12 signalling may play an important role in neutrophil retention at inflammatory sites, identifying a potential new target for the therapeutic removal of neutrophils from the lung in chronic inflammatory disease.

scholarly journals Drift-Diffusion Analysis of Neutrophil Migration during Inflammation Resolution in a Zebrafish Model

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Geoffrey R. Holmes ◽  
Giles Dixon ◽  
Sean R. Anderson ◽  
Constantino Carlos Reyes-Aldasoro ◽  
Philip M. Elks ◽  
...  
Keyword(s):  
Hypothesis Test ◽  
Neutrophil Migration ◽  
Transgenic Zebrafish ◽  
Random Component ◽  
Drift Diffusion ◽  
Zebrafish Model ◽  
Regression Methods ◽  
Reverse Migration ◽  
Pure Diffusion ◽  
Inflammatory Site

Neutrophils must be removed from inflammatory sites for inflammation to resolve. Recent work in zebrafish has shown neutrophils can migrate away from inflammatory sites, as well as die in situ. The signals regulating the process of reverse migration are of considerable interest, but remain unknown. We wished to study the behaviour of neutrophils during reverse migration, to see whether they moved away from inflamed sites in a directed fashion in the same way as they are recruited or whether the inherent random component of their migration was enough to account for this behaviour. Using neutrophil-driven photoconvertible Kaede protein in transgenic zebrafish larvae, we were able to specifically label neutrophils at an inflammatory site generated by tailfin transection. The locations of these neutrophils over time were observed and fitted using regression methods with two separate models: pure-diffusion and drift-diffusion equations. While a model hypothesis test (theF-test) suggested that the datapoints could be fitted by the drift-diffusion model, implying a fugetaxis process, dynamic simulation of the models suggested that migration of neutrophils away from a wound is better described by a zero-drift, “diffusion” process. This has implications for understanding the mechanisms of reverse migration and, by extension, neutrophil retention at inflammatory sites.

scholarly journals Evaluation of the anti-inflammatory effects of synthesised tanshinone I and isotanshinone I analogues in zebrafish

2019 ◽  
Author(s):  
Matthew J. Foulkes ◽  
Katherine M. Henry ◽  
Stephen A. Renshaw ◽  
Simon Jones
Keyword(s):  
Inflammatory Diseases ◽  
Neutrophil Recruitment ◽  
Chronic Obstructive ◽  
Transgenic Zebrafish ◽  
Zebrafish Model ◽  
General Group ◽  
Obstructive Pulmonary Disease ◽  
Anti Inflammatory ◽  
Antiinflammatory Effects

AbstractDuring inflammation, dysregulated neutrophil behaviour can play a major role in chronic inflammatory diseases such as chronic obstructive pulmonary disease, for which current treatments are generally ineffective. Recently, tanshinones have shown promising antiinflammatory effects by targeting neutrophils in vivo, yet are still an underexplored general group of compounds. Here, an existing six step synthetic route was optimised and used to prepare a small family of substituted tanshinone and isomeric isotanshinone analogues, together with the synthesis of other structurally similar molecules. Evaluation of these using a transgenic zebrafish model of inflammation revealed that many of these compounds exhibit promising anti-inflammatory effects in vivo. Several compounds affect neutrophil recruitment and/or resolution of neutrophilic inflammation, and broad structure-activity relationships were constructed. In particular, the methoxy-substituted tanshinone 39 specifically accelerates resolution of inflammation without affecting organism host defence, making this a particularly attractive candidate for potential pro-resolution therapeutics. On the other hand, β-lapachones exhibit effects on neutrophil recruitment yet not on resolution. Notable differences in toxicity profiles between compound classes were also observed.

scholarly journals Insulin resistance in patients with psoriasis

2021 ◽  
Vol 17 (7) ◽  
pp. 570-574
Author(s):  
I.V. Pankiv
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Psoriatic Arthritis ◽  
Systemic Inflammation ◽  
Polycystic Ovary ◽  
Developed Countries ◽  
Low Grade ◽  
Nonalcoholic Fatty Liver ◽  
Systemic Inflammatory Disease

Psoriasis is a chronic systemic inflammatory disease accompanied by an activation of skin dendritic cells with accumulation in the inflammatory foci of interleukin-23 and activated Th-1 lymphocytes (Th-17, Th-22). In recent years, there has been a large number of evidence linking psoriasis with other inflammatory diseases, including obesity, diabetes mellitus, atherosclerosis, hypertension, nonalcoholic fatty liver disease, polycystic ovary syndrome, benign prostatic hyperplasia, etc. All of these conditions are associated with systemic inflammation and insulin resistance induced by it. Psoriasis is the most common chronic dermatosis and affects 1–2 % of the population in developed countries. Psoriasis as a chronic immune-mediated inflammatory skin disease is often associated with metabolic syndrome and its components such as obesity, hypertension, insulin resistance and dyslipidemia. The risk of developing metabolic syndrome in patients with psoriasis is 40 % higher than in the general population. Psoriasis and metabo­lic syndrome share some pathogenic mechanisms such as chronic low-grade systemic inflammation and an increased level of pro-inflammatory cytokines. Systemic inflammation causes obesity, cardiovascular diseases, diabetes mellitus type 2. These conditions increase the risk of mortality among patients with psoriasis. There is a positive correlation between the severity of psoriasis and metabolic syndrome, which is manifested by a severe rash, reduction of the remission and higher risk of psoriatic arthritis development. The carriers of the risk allele of FTO gene are characterized by a more severe psoriasis, the presence of psoriatic arthritis and increased body mass index. A review of the literature focuses on the relationship between insulin resistance and the pathogenesis of psoriasis.

scholarly journals PGE2 production at sites of tissue injury promotes an anti-inflammatory neutrophil phenotype and determines the outcome of inflammation resolution in vivo

2017 ◽  
Author(s):  
Catherine A. Loynes ◽  
Jou A. Lee ◽  
Anne L. Robertson ◽  
Michael JG. Steel ◽  
Felix Ellett ◽  
...  
Keyword(s):  
Tissue Injury ◽  
Neutrophil Migration ◽  
Chronic Inflammatory Disease ◽  
Lipid Mediator ◽  
Prostaglandin E ◽  
Zebrafish Model ◽  
Reverse Migration ◽  
Anti Inflammatory ◽  
Inflammation Resolution

AbstractNeutrophils are the first immune cells recruited to a site of injury or infection, where they perform many functions. Having completed their role, neutrophils must be removed from the inflammatory site - either by apoptosis and efferocytosis or by reverse migration away from the wound - for restoration of normal tissue homeostasis. Disruption of these tightly controlled physiological processes of neutrophil removal can lead to a range of inflammatory diseases. We used an in vivo zebrafish model to understand the role of lipid mediator production in neutrophil removal. Following tailfin amputation in the absence of macrophages, neutrophillic inflammation does not resolve. This is due to loss of macrophage-dependent production of eicosanoid prostaglandin E2, which drives neutrophil removal via promotion of reverse migration. Knockdown of endogenous prostaglandin E synthase gene reveals PGE2 as essential for neutrophil inflammation resolution. Furthermore, PGE2 is able to signal through EP4 receptors to enhance Alox15 production, causing a switch towards anti-inflammatory eicosanoid signalling, specifically Lipoxin A4. Our data confirm regulation of neutrophil migration by PGE2 and LXA4 in an in vivo model of inflammation resolution. This pathway may contain therapeutic targets for driving inflammation resolution in chronic inflammatory disease.

scholarly journals Mycobacterial infection-induced miR-206 inhibits protective neutrophil recruitment via the CXCL12/CXCR4 signalling axis

2021 ◽  
Vol 17 (4) ◽  
pp. e1009186
Author(s):  
Kathryn Wright ◽  
Kumudika de Silva ◽  
Karren M. Plain ◽  
Auriol C. Purdie ◽  
Tamika A. Blair ◽  
...  
Keyword(s):  
Mycobacterial Infection ◽  
Neutrophil Recruitment ◽  
Signalling Pathways ◽  
Zebrafish Embryos ◽  
Bacterial Burden ◽  
Zebrafish Model ◽  
Dynamic Regulation ◽  
Mycobacterial Infections ◽  
Neutrophil Response

Pathogenic mycobacteria actively dysregulate protective host immune signalling pathways during infection to drive the formation of permissive granuloma microenvironments. Dynamic regulation of host microRNA (miRNA) expression is a conserved feature of mycobacterial infections across host-pathogen pairings. Here we examine the role of miR-206 in the zebrafish model of Mycobacterium marinum infection, which allows investigation of the early stages of granuloma formation. We find miR-206 is upregulated following infection by pathogenic M. marinum and that antagomir-mediated knockdown of miR-206 is protective against infection. We observed striking upregulation of cxcl12a and cxcr4b in infected miR-206 knockdown zebrafish embryos and live imaging revealed enhanced recruitment of neutrophils to sites of infection. We used CRISPR/Cas9-mediated knockdown of cxcl12a and cxcr4b expression and AMD3100 inhibition of Cxcr4 to show that the enhanced neutrophil response and reduced bacterial burden caused by miR-206 knockdown was dependent on the Cxcl12/Cxcr4 signalling axis. Together, our data illustrate a pathway through which pathogenic mycobacteria induce host miR-206 expression to suppress Cxcl12/Cxcr4 signalling and prevent protective neutrophil recruitment to granulomas.

scholarly journals Mycobacterial infection-induced miR-206 inhibits protective neutrophil recruitment via the CXCL12/CXCR4 signalling axis

2020 ◽  
Author(s):  
Kathryn Wright ◽  
Kumudika de Silva ◽  
Karren M. Plain ◽  
Auriol C. Purdie ◽  
Tamika A Blair ◽  
...  
Keyword(s):  
Mycobacterial Infection ◽  
Neutrophil Recruitment ◽  
Zebrafish Model ◽  
Dynamic Regulation ◽  
Mycobacterial Infections ◽  
Neutrophil Response ◽  
Significant Disease ◽  
Insight Into ◽  
Highly Evolved

AbstractPathogenic mycobacteria actively dysregulate protective host immune signalling pathways during infection to drive the formation of permissive granuloma microenvironments. Dynamic regulation of host microRNA (miRNA) expression is a conserved feature of mycobacterial infections across host-pathogen pairings. Here we examine the role of miR-206 in the zebrafish model of Mycobacterium marinum infection, which allows investigation of the early stages of granuloma formation. We find miR-206 is upregulated following infection by pathogenic M. marinum and that antagomir-mediated knockdown of miR-206 is protective against infection. We observed striking upregulation of cxcl12a and cxcr4b in infected miR-206 knockdown zebrafish embryos and live imaging revealed enhanced recruitment of neutrophils to sites of infection. We used Crispr/Cas9-mediated knockdown of cxcl12a and cxcr4b expression and AMD3100 inhibition of Cxcr4 to show that the enhanced neutrophil response and reduced bacterial burden caused by miR-206 knockdown was dependent on the Cxcl12/Cxcr4 signalling axis. Together, our data illustrate a pathway through which pathogenic mycobacteria induce host miR-206 expression to suppress Cxcl12/Cxcr4 signalling and prevent protective neutrophil recruitment to granulomas.Author summaryMycobacterial infections cause significant disease burden to humans and animals, the most widely known example being tuberculosis which has killed more humans than any other infectious disease throughout history. Infectious mycobacteria are highly evolved to hijack host processes, including the very immune cells tasked with destroying them. microRNAs are host molecules that control wide-ranging programs of host gene expression and are important in the immune response to infections. Here we use the zebrafish model of mycobacterial infection to determine the role of the infection-induced microRNA miR-206 in the host response to infection. We found pathogenic mycobacteria trigger the host to produce more miR-206 in order to suppress the otherwise protective recruitment of neutrophils to sites of infection via the host Cxcl12/Cxcr4 signalling pathway. Our study provides new insight into the role of mycobacterial infection-induced miR-206 function in the context of a whole host.

STUDY OF HS-CRP AND TNF-A LEVELS IN COPD PATIENTS ACCOMPANIED WITH CORONARY ARTERY DISEASE

2014 ◽  
pp. 48-56
Author(s):  
Van Thi Tran ◽  
Van Bang Le ◽  
Thị Thu Huong Hoang
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Systemic Inflammation ◽  
Chronic Obstructive ◽  
Low Grade ◽  
Cross Sectional ◽  
Copd Patients ◽  
Coronary Artery Angiography ◽  
Hs Crp ◽  
Artery Disease

Aim: Some studies have linked the present of chronic obstructive oulmonary disease (COPD) to coronary artery disease (CAD). Low grade systemic inflammation occurs in patients with COPD as well as patients with CAD. This study was designed to find out the concentration differences of hs-CRP and TNF-a in patients having both chronic obstructive pulmonary and coronary artery diseases with those having either. Methods: A cross - sectional descriptive study was conducted in 200 patients undergoing a coronary artery angiography in the Heart Institute, Thong Nhat Hospital and 115 People Hospital. COPD was diagnosed using GOLD classification. Result: Our study had shown that the levels of hs-CRP and TNF-a were statistically increased in patients with COPD, CAD as well as in patients who had COPD with CAD (p<0,05). The levels of hs-CRP were higher in CAD than in COPD nad the levels of TNF-a were higher in COPD than in CAD. In patients with COPD and CAD, there were increased the levels of both hs-CRP and TNF-a in serum. Conclusion: Systemic inflammation presents in both COPD and CAD. Key words: hs-CRP, TNF-a, coronary artery disease (CAD).

scholarly journals MicroRNA-21 Plays Multiple Oncometabolic Roles in the Process of NAFLD-Related Hepatocellular Carcinoma via PI3K/AKT, TGF-β, and STAT3 Signaling

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 940
Author(s):  
Chi-Yu Lai ◽  
Kun-Yun Yeh ◽  
Chiu-Ya Lin ◽  
Yang-Wen Hsieh ◽  
Hsin-Hung Lai ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathways ◽  
Stellate Cell ◽  
Human Cancer ◽  
Tumor Formation ◽  
Transgenic Zebrafish ◽  
Zebrafish Model ◽  
Lipid Metabolism Disorder ◽  
Full Spectrum ◽  
Stat3 Signaling

MicroRNA-21 (miR-21) is one of the most frequently upregulated miRNAs in liver diseases such as nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC). However, mechanistic pathways that connect NAFLD and HCC remain elusive. We developed a doxycycline (Dox)-inducible transgenic zebrafish model (LmiR21) which exhibited an upregulation of miR-21 in the liver, which in turn induced the full spectrum of NAFLD, including steatosis, inflammation, fibrosis, and HCC, in the LmiR21 fish. Diethylnitrosamine (DEN) treatment led to accelerated liver tumor formation and exacerbated their aggressiveness. Moreover, prolonged miR-21 expression for up to ten months induced nonalcoholic steatohepatitis (NASH)-related HCC (NAHCC). Immunoblotting and immunostaining confirmed the presence of miR-21 regulatory proteins (i.e., PTEN, SMAD7, p-AKT, p-SMAD3, and p-STAT3) in human nonviral HCC tissues and LmiR21 models. Thus, we demonstrated that miR-21 can induce NAHCC via at least three mechanisms: First, the occurrence of hepatic steatosis increases with the decrease of ptenb, pparaa, and activation of the PI3K/AKT pathway; second, miR-21 induces hepatic inflammation (or NASH) through an increase in inflammatory gene expression via STAT3 signaling pathways, and induces liver fibrosis through hepatic stellate cell (HSC) activation and collagen deposition via TGF-β/Smad3/Smad7 signaling pathways; finally, oncogenic activation of Smad3/Stat3 signaling pathways induces HCC. Our LmiR21 models showed similar molecular pathology to the human cancer samples in terms of initiation of lipid metabolism disorder, inflammation, fibrosis and activation of the PI3K/AKT, TGF-β/SMADs and STAT3 (PTS) oncogenic signaling pathways. Our findings indicate that miR-21 plays critical roles in the mechanistic perspectives of NAHCC development via the PTS signaling networks.

scholarly journals Author Correction: Stimulation of hepatocarcinogenesis by activated cholangiocytes via Il17a/f1 pathway in kras transgenic zebrafish model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mohamed Helal ◽  
Chuan Yan ◽  
Zhiyuan Gong
Keyword(s):  
Transgenic Zebrafish ◽  
Zebrafish Model ◽  
Stimulation Of

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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