scholarly journals Immune-Mediated Retinal Vasculitis in Posterior Uveitis and Experimental Models: The Leukotriene (LT)B4-VEGF Axis

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 396
Author(s):  
Malihe Eskandarpour ◽  
Miles A. Nunn ◽  
Wynne Weston-Davies ◽  
Virginia L. Calder
Keyword(s):  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Retinal Vasculitis ◽  
Vascular Diseases ◽  
Leukotriene B4 ◽  
Experimental Models ◽  
Posterior Uveitis ◽  
Angiogenic Factor ◽  
Immune Mediated ◽  
Endothelial Growth Factor

Retinal vascular diseases have distinct, complex and multifactorial pathogeneses yet share several key pathophysiological aspects including inflammation, vascular permeability and neovascularisation. In non-infectious posterior uveitis (NIU), retinal vasculitis involves vessel leakage leading to retinal enlargement, exudation, and macular oedema. Neovascularisation is not a common feature in NIU, however, detection of the major angiogenic factor—vascular endothelial growth factor A (VEGF-A)—in intraocular fluids in animal models of uveitis may be an indication for a role for this cytokine in a highly inflammatory condition. Suppression of VEGF-A by directly targeting the leukotriene B4 (LTB4) receptor (BLT1) pathway indicates a connection between leukotrienes (LTs), which have prominent roles in initiating and propagating inflammatory responses, and VEGF-A in retinal inflammatory diseases. Further research is needed to understand how LTs interact with intraocular cytokines in retinal inflammatory diseases to guide the development of novel therapeutic approaches targeting both inflammatory mediator pathways.

Nuclear receptor Nur77: its role in chronic inflammatory diseases

2021 ◽  
Author(s):  
Sanne C. Lith ◽  
Carlie J.M. de Vries
Keyword(s):  
Nuclear Receptor ◽  
Inflammatory Disease ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Experimental Models ◽  
Therapeutic Interventions ◽  
Alternative Mechanism ◽  
Signaling Complex

Abstract Nur77 is a nuclear receptor that has been implicated as a regulator of inflammatory disease. The expression of Nur77 increases upon stimulation of immune cells and is differentially expressed in chronically inflamed organs in human and experimental models. Furthermore, in a variety of animal models dedicated to study inflammatory diseases, changes in Nur77 expression alter disease outcome. The available studies comprise a wealth of information on the function of Nur77 in diverse cell types and tissues. Negative cross-talk of Nur77 with the NFκB signaling complex is an example of Nur77 effector function. An alternative mechanism of action has been established, involving Nur77-mediated modulation of metabolism in macrophages as well as in T cells. In this review, we summarize our current knowledge on the role of Nur77 in atherosclerosis, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and sepsis. Detailed insight in the control of inflammatory responses will be essential in order to advance Nur77-targeted therapeutic interventions in inflammatory disease.

scholarly journals DNA damage independent inhibition of NF-κB transcription by anthracyclines

2020 ◽  
Author(s):  
Angelo Chora ◽  
Dora Pedroso ◽  
Nadja Pejanovic ◽  
Eleni Kyriakou ◽  
Henrique Colaço ◽  
...  
Keyword(s):  
Dna Damage ◽  
Transcription Factors ◽  
Binding Sites ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Anticancer Properties ◽  
Dna Binding Sites ◽  
Immune Mediated ◽  
Life Threatening ◽  
Molecular Patterns

AbstractTranscriptional programs leading to induction of a large number of genes can be rapidly initiated by the activation of only few selected transcription factors. Upon stimulation of macrophages with microbial-associated molecular patterns (MAMPs), the activation of the nuclear factor kappa B (NF-κB) family of transcription factors triggers inflammatory responses that, left uncontrolled, can lead to excessive inflammation with life-threatening consequences for the host. Here we identify and characterize a novel effect of Anthracyclines, a class of drugs currently used as potent anticancer drugs, in the regulation of NF-κB transcriptional activity in BMDMs, in addition to the previously reported DNA damage and histone eviction. Anthracyclines, including Doxorubicin, Daunorubicin and Epirubicin, disturb the complexes formed between the NF-κB subunit RelA and its DNA binding sites, to limit NF-κB-dependent gene transcription during inflammatory responses, including of pivotal pro-inflammatory mediators such as TNF. We observed that suppression of inflammation can also be mediated by Aclarubicin, Doxorubicinone and the newly developed Dimethyl-doxorubicin, which share anticancer properties with the other Anthracyclines, but do not induce DNA damage in the tested concentrations. This novel mechanism of action of Anthracyclines, contributing to the reduction of inflammation, is thus independent of the activation of DNA damage responses and may be relevant for the development of novel strategies targeting immune-mediated inflammatory diseases.

scholarly journals Unfulfilled Inflammatory Resolution: A Key Factor in the Pathogenesis of Psoriasis

2020 ◽  
Author(s):  
Zohreh Jadali
Keyword(s):  
Inflammatory Response ◽  
Chronic Inflammation ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Relevant Literature ◽  
Regulatory Mechanisms ◽  
Immune Mediated ◽  
Key Factor ◽  
Inflammation Resolution

Recent literature has highlighted the importance of chronic inflammation in psoriasis pathogenesis. Non-resolving inflammation can trigger progressive tissue damage and inflammatory mediator release which in turn perpetuate the inflammatory cycle. Under normal conditions, inflammatory responses are tightly controlled through several mechanisms that restore normal tissue function and structure. Defects in regulatory mechanisms of the inflammatory response can result in persistent unresolved inflammation and further increases of inflammation. Therefore, this review focuses on defects in regulatory mechanisms of inflammatory responses that lead to uncontrolled chronic inflammation in psoriasis. Databases such as Pubmed Embase, ISI, and Iranian databases including Iranmedex, and SID were researched to identify relevant literature. The results of this review indicate that dysregulation of the inflammatory response may be a likely cause of various immune-mediated inflammatory disorders such as psoriasis. Based on current findings, advances in understanding the cellular and molecular mechanisms involved in inflammation resolution are not only improving our knowledge of the pathogenesis of chronic inflammatory diseases but also supporting the development of new therapeutic strategies.

scholarly journals An Important Role of Blood and Lymphatic Vessels in Inflammation and Allergy

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Silvana Zgraggen ◽  
Alexandra M. Ochsenbein ◽  
Michael Detmar
Keyword(s):  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Experimental Studies ◽  
Lymphatic Vessels ◽  
Allergic Inflammation ◽  
Skin Inflammation ◽  
Chronic Inflammatory Diseases ◽  
Chronic Skin ◽  
Targeted Inhibition ◽  
Endothelial Growth Factor

Angiogenesis and lymphangiogenesis, the growth of new vessels from preexisting ones, have received increasing interest due to their role in tumor growth and metastatic spread. However, vascular remodeling, associated with vascular hyperpermeability, is also a key feature of many chronic inflammatory diseases including asthma, atopic dermatitis, psoriasis, and rheumatoid arthritis. The major drivers of angiogenesis and lymphangiogenesis are vascular endothelial growth factor- (VEGF-)A and VEGF-C, activating specific VEGF receptors on the lymphatic and blood vascular endothelium. Recent experimental studies found potent anti-inflammatory responses after targeted inhibition of activated blood vessels in models of chronic inflammatory diseases. Importantly, our recent results indicate that specific activation of lymphatic vessels reduces both acute and chronic skin inflammation. Thus, antiangiogenic and prolymphangiogenic therapies might represent a new approach to treat chronic inflammatory disorders, including those due to chronic allergic inflammation.

Increased plasma levels of pentraxin 3 in patients with multiple sclerosis and neuromyelitis optica

2012 ◽  
Vol 19 (7) ◽  
pp. 926-931 ◽  
Author(s):  
Honghao Wang ◽  
Kai Wang ◽  
Conghui Wang ◽  
Xiaonan Zhong ◽  
Wei Qiu ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Neuromyelitis Optica ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Vascular Diseases ◽  
Enzyme Linked Immunosorbent Assay ◽  
Pentraxin 3 ◽  
Inflammatory Protein ◽  
Ptx3 Level ◽  
Headache Patients

Background: Multiple sclerosis (MS) and neuromyelitis optica (NMO) are immune-mediated inflammatory diseases of the central nervous system. In the acute phase of these diseases, secondary ischemia due to inflammation-induced endothelial dysfunction may be an important pathological change. Pentraxin 3 (PTX3) is a pro-inflammatory protein and a novel biomarker of inflammatory vascular diseases. Objective: We aimed to determine whether PTX3 levels are elevated in MS and NMO patients. Methods: The concentrations of plasma PTX3 were measured using an enzyme-linked immunosorbent assay in 22 MS patients, 26 NMO patients, 15 acute cerebral infarction (CI) patients, 11 mild headache patients, and 14 volunteer controls. Results: During relapse, plasma PTX3 levels were higher in MS patients than in headache patients ( p=0.003) and controls ( p<0.001). Plasma PTX3 levels were also increased in NMO patients compared with CI patients ( p=0.011), headache patients ( p<0.001) and controls ( p<0.001). CI patients showed elevated PTX3 levels compared with controls ( p=0.008). MS and NMO patients showed a trend toward an increased disease disability with higher plasma PTX3 during relapse (MS: p=0.005; NMO: p<0.001). Plasma PTX3 levels were remarkably lower in remission than in the relapse stage (MS: p<0.001; NMO: p<0.001). Conclusion: Plasma PTX3 level is associated with inflammatory responses in MS and NMO.

scholarly journals THU0311 CERTOLIZUMAB THERAPY IN REFRACTORY UVEITIS DUE TO IMMUNE-MEDIATED INFLAMMATORY DISEASES (IMID). MULTICENTER STUDY OF 39 PATIENTS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 384.2-385
Author(s):  
J. L. Martín-Varillas ◽  
V. Calvo-Río ◽  
L. Sanchez-Bilbao ◽  
I. González-Mazón ◽  
I. Torre-Salaberri ◽  
...  
Keyword(s):  
Multicenter Study ◽  
Inflammatory Diseases ◽  
Certolizumab Pegol ◽  
Oral Prednisone ◽  
Retinal Vasculitis ◽  
Relapsing Polychondritis ◽  
Research Support ◽  
Biological Drugs ◽  
Immune Mediated ◽  
Adalimumab Therapy

Background:Infliximab and adalimumab therapy has significantly improved the prognosis of patients with non-infectious refractory uveitis. However, there is not enough evidence for the use of other anti-TNF drugs such as Certolizumab Pegol (CZP).Objectives:To evaluate the efficacy and safety of CZP in uveitis secondary to Immune-Mediated Inflammatory Diseases (IMID).Methods:Multicenter study of 39 patients with uveitis due to IMID refractory to glucocorticoids and conventional immunosuppressants. Efficacy of CZP was evaluated with the following ocular parameters: best corrected visual acuity (BCVA), anterior chamber cells, macular thickness and presence of retinal vasculitis. Efficacy of CZP was compared between baseline, 1st week, 1st and 6th month, and 1st and 2nd year. Statistical analysis was performed with the STATISTICA software (Statsoft Inc. Tulsa, Oklahoma, USA).Results:39 patients/56 affected eyes (18 men/21 women) with a mean age of 40.5±11.9 years were studied. IMIDs included were: spondyloarthritis (n=17), psoriatic arthritis (6), Crohn (3), JIA (2), Behçet (2), reactive arthritis (2), rheumatoid arthritis (1), relapsing polychondritis (1), pars planitis (1), Birdshot (1) and idiopathic uveitis (3). Uveitis pattern was as follows: anterior (n=30), posterior (4), panuveitis (3) and intermediate (2).Previous CZP, patients received: oral prednisone (n=18) methylprednisolone bolus (1), methotrexate (22), azathioprine (10), cyclosporine (4), leflunomide (2), mycophenolate mofetil (2) and cyclophosphamide (1). 77% of patients had received previous biological therapy, with a mean of 1.6±1.2 biological drugs per patient. Gestational desire was the reason for prescribing CZP in 8 patients. CZP was administered in monotherapy in 16 patients and in the remaining 23 patients combined with conventional immunosuppressants.After a median follow-up of 24 [6-36] months, most of the ocular variables analysed showed a rapid and significantly sustained improvement (Table). CZP was discontinued in 11 patients for the following reasons: remission (n=1), insufficient response of ocular symptoms (n=1) and limited response of extraocular manifestations (n=9). No serious adverse effects were reported.Conclusion:CZP seems to be effective and safe in patients with refractory uveitis due to IMID.TableBaseline1stweek1stMonth6thMonth1styear2ndyearBCVA (mean±SD)0.77±0.290.77±0.30*0.82±0.29*0.85±0.26*0.86±0.27*0.88±0.23*Tyndall (median [IQR])0 [0-2]0 [0-2]0 [0-1]*0 [0-0]*0 [0-0]*0 [0-0]*OCT (mean±SD)355±61.5-284.1±40.4*-224.8±121.1*-Retinal Vasculitis (eyes affected, %)2 (3.6)0 (0)0 (0)0 (0)0 (0)0 (0)*p<0.05Disclosure of Interests:José Luis Martín-Varillas Grant/research support from: AbbVie, Pfizer, Janssen and Celgene, Speakers bureau: Pfizer and Lilly, Vanesa Calvo-Río Grant/research support from: MSD and Roche, Speakers bureau: AbbVie, Lilly, Celgene, Grünenthal, UCB Pharma, Lara Sanchez-Bilbao Grant/research support from: Pfizer, Iñigo González-Mazón: None declared, Ignacio Torre-Salaberri: None declared, Álvaro García Martos: None declared, Amalia Sanchez-Andrade: None declared, Ángel García-Aparicio: None declared, JR De Dios-Jiménez Aberásturi: None declared, ANA URRUTICOECHEA-ARANA: None declared, Olga Maíz: None declared, Raul Veroz Gonzalez: None declared, Andrea García-Valle: None declared, Sergio Rodríguez Montero: None declared, Roberto Miguélez: None declared, Vega Jovani: None declared, Marisa Hernández-Garfella: None declared, Arantxa Conesa: None declared, Olga Martínez González: None declared, Paula Rubio Muñoz: None declared, Belén Atienza-Mateo: None declared, Miguel A González-Gay Grant/research support from: Pfizer, Abbvie, MSD, Speakers bureau: Pfizer, Abbvie, MSD, Ricardo Blanco Grant/research support from: AbbVie, MSD, and Roche, Speakers bureau: AbbVie, Pfizer, Roche, Bristol-Myers, Janssen, and MSD

scholarly journals Lysosomal amino acid transporters as key players in inflammatory diseases

2021 ◽  
Author(s):  
Noriko Toyama-Sorimachi ◽  
Toshihiko Kobayashi
Keyword(s):  
Signal Transduction ◽  
Amino Acid ◽  
Immune Cells ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Metabolic Adaptation ◽  
Amino Acid Transporters ◽  
Proof Of Concept ◽  
Immune Mediated ◽  
Solute Carrier

Abstract Controlling inflammation can alleviate immune-mediated, lifestyle-related and neurodegenerative diseases. The endolysosome system plays critical roles in inflammatory responses. Endolysosomes function as signal transduction hubs to convert various environmental danger signals into gene expression, enabling metabolic adaptation of immune cells and efficient orchestration of inflammation. Solute carrier family 15 member 3 (SLC15A3) and member 4 (SLC15A4) are endolysosome-resident amino acid transporters that are preferentially expressed in immune cells. These transporters play essential roles in signal transduction through endolysosomes, and the loss of either transporter can alleviate multiple inflammatory diseases because of perturbed endolysosome-dependent signaling events, including inflammatory and metabolic signaling. Here, we summarize the findings leading to a proof-of-concept for anti-inflammatory strategies based on targeting SLC15 transporters.

Toll-Like Receptor 4 (TLR4) and AMPK Relevance in Cardiovascular Disease

2021 ◽  
Author(s):  
Haleh Vaez ◽  
Hamid Soraya ◽  
Alireza Garjani ◽  
Tooba Gholikhani
Keyword(s):  
Cardiovascular Diseases ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Adenosine Monophosphate ◽  
Ampk Signaling ◽  
Inflammatory Conditions ◽  
Immune Mediated ◽  
Energy Sensor

Toll-like receptors (TLRs) are essential receptors of the innate immune system, playing a significant role in cardiovascular diseases. TLR4, with the highest expression among TLRs in the heart, has been investigated extensively for its critical role in different myocardial inflammatory conditions. Studies suggest that inhibition of TLR4 signaling pathways reduces inflammatory responses and even prevents additional injuries to the already damaged myocardium. Recent research results have led to a hypothesis that there may be a relation between TLR4 expression and 5' adenosine monophosphate-activated protein kinase (AMPK) signaling in various inflammatory conditions, including cardiovascular diseases. AMPK, as a cellular energy sensor, has been reported to show anti-inflammatory effects in various models of inflammatory diseases. AMPK, in addition to its physiological acts in the heart, plays an essential role in myocardial ischemia and hypoxia by activating various energy production pathways. Herein we will discuss the role of TLR4 and AMPK in cardiovascular diseases and a possible relation between TLRs and AMPK as a novel therapeutic target. In our opinion, AMPK-related TLR modulators will find application in treating different immune-mediated inflammatory disorders, especially inflammatory cardiac diseases, and present an option that will be widely used in clinical practice in the future.

scholarly journals The PAR2 inhibitor I-287 selectively targets Gαq and Gα12/13 signaling and has anti-inflammatory effects

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Charlotte Avet ◽  
Claudio Sturino ◽  
Sébastien Grastilleur ◽  
Christian Le Gouill ◽  
Meriem Semache ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Selective Inhibition ◽  
Downstream Effectors ◽  
Immune Mediated ◽  
Promising Therapeutic Target ◽  
Protease Activated Receptor 2 ◽  
Multiple Signaling

AbstractProtease-activated receptor-2 (PAR2) is involved in inflammatory responses and pain, therefore representing a promising therapeutic target for the treatment of immune-mediated inflammatory diseases. However, as for other GPCRs, PAR2 can activate multiple signaling pathways and those involved in inflammatory responses remain poorly defined. Here, we describe a new selective and potent PAR2 inhibitor (I-287) that shows functional selectivity by acting as a negative allosteric regulator on Gαq and Gα12/13 activity and their downstream effectors, while having no effect on Gi/o signaling and βarrestin2 engagement. Such selective inhibition of only a subset of the pathways engaged by PAR2 was found to be sufficient to block inflammation in vivo. In addition to unraveling the PAR2 signaling pathways involved in the pro-inflammatory response, our study opens the path toward the development of new functionally selective drugs with reduced liabilities that could arise from blocking all the signaling activities controlled by the receptor.

scholarly journals Immune Modulation as Adjunctive Therapy forPneumocystispneumonia

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Jing Wang ◽  
Terry W. Wright ◽  
Francis Gigliotti
Keyword(s):  
Immune Modulation ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Respiratory Pathogen ◽  
Cell Mediated Immunity ◽  
Clinical Settings ◽  
Immune Mediated ◽  
Life Threatening ◽  
Acquired Immunodeficiency ◽  
Immunodeficiency Syndrome

Pneumocystisis an opportunistic fungal respiratory pathogen that causes life-threatening pneumonia (Pcp) in patients suffering from defects in cell-mediated immunity, including those with acquired immunodeficiency syndrome (AIDS) and immunosuppression secondary to chemotherapy or organ transplantation. Despite major advances in health care, the mortality associated with Pcp has changed little over the past 25  years. Pcp remains a leading cause of death among HIV infected patients, with mortality rates of 50% or higher for patients developing severe Pcp. In addition, as more potent immunosuppressive therapies are developed for chronic inflammatory diseases, more cases of Pcp are occurring in non-HIV patients and in previously unreported clinical settings. These features highlight the importance of developing a better understanding of the pathogenesis of this disease, and the need to search for new therapeutic strategies to improve the outcome of Pcp patients. Immune-mediated inflammatory responses play an important role in the pathogenesis of Pcp, and may be even more significant in determining the outcome of Pcp than direct damage due to the organism itself. In this review we will summarize the immunopathogenic mechanisms that contribute to Pcp-associated lung injury, and discuss the potential to target these pathways for adjunctive immune modulation therapy for Pcp.

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