scholarly journals Targeting the chemokine receptor CXCR4 with histamine analogue to reduce inflammation in juvenile arthritis: a proof of concept for COVID-19 therapeutic approach

2021 ◽  
Author(s):  
Nassima Bekaddour ◽  
Nikaia Smith ◽  
Benoit Beitz ◽  
Alba Llibre ◽  
Tom Dott ◽  
...  
Keyword(s):  
Immune Cell ◽  
Inflammatory Diseases ◽  
Therapeutic Option ◽  
Critical Role ◽  
Inflammatory Factors ◽  
Amino Compound ◽  
Cytokine Storm ◽  
Inflammatory Monocytes ◽  
Current Therapies ◽  
Activated Monocytes

Among immune cells, activated monocytes play a detrimental role in chronic and viral-induced inflammatory pathologies. The uncontrolled activation of monocytes and the subsequent excessive production of inflammatory factors damage bone-cartilage joints in Juvenile Idiopathic Arthritis (JIA), a childhood rheumatoid arthritis (RA) disease. Inflammatory monocytes also exert a critical role in the cytokine storm induced by SARS-CoV2 infection in severe COVID-19 patients. The moderate beneficial effect of current therapies and clinical trials highlights the need of alternative strategies targeting monocytes to treat RA and COVID-19 pathologies. Here, we show that targeting CXCR4 with small amino compound such as the histamine analogue clobenpropit (CB) inhibits spontaneous and induced-production of a set of key inflammatory cytokines by monocytes isolated from blood and synovial fluids of JIA patients. Moreover, daily intraperitoneal CB treatment of arthritic mice results in significant decrease in circulating inflammatory cytokine levels, immune cell infiltrates, joints erosion, and bone resorption leading to reduction of disease progression. Finally, we provide the prime evidence that the exposure of whole blood from hospitalized COVID-19 patients to CB significantly reduces levels of key cytokine-storm-associated factors including TNF-α, IL-6 and IL-1β. These overall data show that targeting CXCR4 with CB-like molecules may represent a promising therapeutic option for chronic and viral-induced inflammatory diseases.

scholarly journals The Effect and Regulatory Mechanism of High Mobility Group Box-1 Protein on Immune Cells in Inflammatory Diseases

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1044
Author(s):  
Yun Ge ◽  
Man Huang ◽  
Yong-ming Yao
Keyword(s):  
Immune Cells ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
High Mobility ◽  
Cell Types ◽  
High Mobility Group ◽  
High Mobility Group Protein

High mobility group box-1 protein (HMGB1), a member of the high mobility group protein superfamily, is an abundant and ubiquitously expressed nuclear protein. Intracellular HMGB1 is released by immune and necrotic cells and secreted HMGB1 activates a range of immune cells, contributing to the excessive release of inflammatory cytokines and promoting processes such as cell migration and adhesion. Moreover, HMGB1 is a typical damage-associated molecular pattern molecule that participates in various inflammatory and immune responses. In these ways, it plays a critical role in the pathophysiology of inflammatory diseases. Herein, we review the effects of HMGB1 on various immune cell types and describe the molecular mechanisms by which it contributes to the development of inflammatory disorders. Finally, we address the therapeutic potential of targeting HMGB1.

scholarly journals IFN-γ and TNF-α drive a CXCL10+ CCL2+ macrophage phenotype expanded in severe COVID-19 lungs and inflammatory diseases with tissue inflammation

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Fan Zhang ◽  
◽  
Joseph R. Mears ◽  
Lorien Shakib ◽  
Jessica I. Beynor ◽  
...  
Keyword(s):  
Single Cell ◽  
Immune Cell ◽  
Inflammatory Diseases ◽  
Interferon Response ◽  
Inflammatory Factors ◽  
Macrophage Phenotype ◽  
Tnf Α ◽  
Ifn Γ ◽  
Immunomodulatory Therapies ◽  
Inflammatory Macrophage

Abstract Background Immunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19. Understanding the immune cell states shared between COVID-19 and other inflammatory diseases with established therapies may help nominate immunomodulatory therapies. Methods To identify cellular phenotypes that may be shared across tissues affected by disparate inflammatory diseases, we developed a meta-analysis and integration pipeline that models and removes the effects of technology, tissue of origin, and donor that confound cell-type identification. Using this approach, we integrated > 300,000 single-cell transcriptomic profiles from COVID-19-affected lungs and tissues from healthy subjects and patients with five inflammatory diseases: rheumatoid arthritis (RA), Crohn’s disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE), and interstitial lung disease. We tested the association of shared immune states with severe/inflamed status compared to healthy control using mixed-effects modeling. To define environmental factors within these tissues that shape shared macrophage phenotypes, we stimulated human blood-derived macrophages with defined combinations of inflammatory factors, emphasizing in particular antiviral interferons IFN-beta (IFN-β) and IFN-gamma (IFN-γ), and pro-inflammatory cytokines such as TNF. Results We built an immune cell reference consisting of > 300,000 single-cell profiles from 125 healthy or disease-affected donors from COVID-19 and five inflammatory diseases. We observed a CXCL10+ CCL2+ inflammatory macrophage state that is shared and strikingly abundant in severe COVID-19 bronchoalveolar lavage samples, inflamed RA synovium, inflamed CD ileum, and UC colon. These cells exhibited a distinct arrangement of pro-inflammatory and interferon response genes, including elevated levels of CXCL10, CXCL9, CCL2, CCL3, GBP1, STAT1, and IL1B. Further, we found this macrophage phenotype is induced upon co-stimulation by IFN-γ and TNF-α. Conclusions Our integrative analysis identified immune cell states shared across inflamed tissues affected by inflammatory diseases and COVID-19. Our study supports a key role for IFN-γ together with TNF-α in driving an abundant inflammatory macrophage phenotype in severe COVID-19-affected lungs, as well as inflamed RA synovium, CD ileum, and UC colon, which may be targeted by existing immunomodulatory therapies.

scholarly journals mTORC1-Activated Monocytes Increase Tregs and Inhibit the Immune Response to Bacterial Infections

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Lijun Fang ◽  
Huaijun Tu ◽  
Wei Guo ◽  
Shixuan Wang ◽  
Ting Xue ◽  
...  
Keyword(s):  
Immune Response ◽  
Bacterial Infections ◽  
Immune Cell ◽  
Critical Role ◽  
Innate Immune ◽  
E Coli ◽  
Upstream Regulator ◽  
Mtorc1 Signaling ◽  
Activated Monocytes ◽  
Mtorc1 Activation

The TSC1/2 heterodimer, a key upstream regulator of the mTOR, can inhibit the activation of mTOR, which plays a critical role in immune responses after bacterial infections. Monocytes are an innate immune cell type that have been shown to be involved in bacteremia. However, how the mTOR pathway is involved in the regulation of monocytes is largely unknown. In our study, TSC1 KO mice and WT mice were infected withE. coli. When compared to WT mice, we found higher mortality, greater numbers of bacteria, decreased expression of coactivators in monocytes, increased numbers of Tregs, and decreased numbers of effector T cells in TSC1 KO mice. Monocytes obtained from TSC1 KO mice produced more ROS, IL-6, IL-10, and TGF-βand less IL-1, IFN-γ, and TNF-α. Taken together, our results suggest that the inhibited immune functioning in TSC1 KO mice is influenced by mTORC1 activation in monocytes. The reduced expression of coactivators resulted in inhibited effector T cell proliferation. mTORC1-activated monocytes are harmful during bacterial infections. Therefore, inhibiting mTORC1 signaling through rapamycin administration could rescue the harmful aspects of an overactive immune response, and this knowledge provides a new direction for clinical therapy.

Exploiting Anti-Inflammation Effects of Flavonoids in Chronic Inflammatory Diseases

2020 ◽  
Vol 26 (22) ◽  
pp. 2610-2619 ◽  
Author(s):  
Tarique Hussain ◽  
Ghulam Murtaza ◽  
Huansheng Yang ◽  
Muhammad S. Kalhoro ◽  
Dildar H. Kalhoro
Keyword(s):  
Oxidative Stress ◽  
Chronic Diseases ◽  
Inflammatory Diseases ◽  
Therapeutic Option ◽  
Cellular Level ◽  
Antiinflammatory Drugs ◽  
Suitable Alternative ◽  
Chronic Inflammatory Diseases

Background: Inflammation is a complex response of the host defense system to different internal and external stimuli. It is believed that persistent inflammation may lead to chronic inflammatory diseases such as, inflammatory bowel disease, neurological and cardiovascular diseases. Oxidative stress is the main factor responsible for the augmentation of inflammation via various molecular pathways. Therefore, alleviating oxidative stress is effective a therapeutic option against chronic inflammatory diseases. Methods: This review article extends the knowledge of the regulatory mechanisms of flavonoids targeting inflammatory pathways in chronic diseases, which would be the best approach for the development of suitable therapeutic agents against chronic diseases. Results: Since the inflammatory response is initiated by numerous signaling molecules like NF-κB, MAPK, and Arachidonic acid pathways, their encountering function can be evaluated with the activation of Nrf2 pathway, a promising approach to inhibit/prevent chronic inflammatory diseases by flavonoids. Over the last few decades, flavonoids drew much attention as a potent alternative therapeutic agent. Recent clinical evidence has shown significant impacts of flavonoids on chronic diseases in different in-vivo and in-vitro models. Conclusion: Flavonoid compounds can interact with chronic inflammatory diseases at the cellular level and modulate the response of protein pathways. A promising approach is needed to overlook suitable alternative compounds providing more therapeutic efficacy and exerting fewer side effects than commercially available antiinflammatory drugs.

Salivary mir-27b Expression in Oral Lichen Planus Patients: A Series of Cases and a Narrative Review of Literature

2020 ◽  
Vol 19 (31) ◽  
pp. 2816-2823 ◽  
Author(s):  
Dario Di Stasio ◽  
Laura Mosca ◽  
Alberta Lucchese ◽  
Donatella Delle Cave ◽  
Hiromichi Kawasaki ◽  
...  
Keyword(s):  
Lichen Planus ◽  
Oral Lichen Planus ◽  
Inflammatory Diseases ◽  
Biological Fluids ◽  
Critical Role ◽  
Invasive Procedure ◽  
Control Group ◽  
Study Group ◽  
Immune Functions ◽  
Oral Lichen

Background: microRNAs play a critical role in auto-immunity, cell proliferation, differentiation and cell death. miRNAs are present in all biological fluids, and their expression is essential in maintaining regular immune functions and preventing autoimmunity, whereas miRNA dysregulation may be associated with the pathogenesis of autoimmune and inflammatory diseases. Oral lichen planus (OLP) is an inflammatory disease mediated by cytotoxic T cells attack against epithelial cells. The present study aims to perform a specific microRNA expression profile through the analysis of saliva in this disease. Methods: The study group was formed by five patients (mean age 62.8±1.98 years; 3 females/2 males) affected by oral lichen planus and control group by five healthy subjects (mean age 59.8 years±2.3; 3 females/ 2 males); using a low-density microarray analysis, we recorded a total of 98 differentially expressed miRNAs in the saliva of patients with oral lichen planus compared to the control group. The validation was performed for miR-27b with qRT-PCR in all saliva samples of oral lichen planus group. Results: 89 miRNAs were up-regulated and nine down-regulated. In details, levels of miR-21, miR- 125b, miR-203 and miR15b were increased (p<0.001) in study group while levels of miR-27b were about 3.0-fold decreased compared to controls (p<0.001) of miR-27b expression in OLP saliva. QRTPCR validation confirmed the down regulation of miR-27b in all saliva samples. Conclusions: Collecting saliva samples is a non-invasive procedure and is well accepted by all patients. microRNAs can be readily isolated and identified and can represent useful biomarkers of OLP.

scholarly journals Paracellular and Transcellular Leukocytes Diapedesis Are Divergent but Interconnected Evolutionary Events

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 254
Author(s):  
Michel-Edwar Mickael ◽  
Norwin Kubick ◽  
Pavel Klimovich ◽  
Patrick Henckell Flournoy ◽  
Irmina Bieńkowska ◽  
...  
Keyword(s):  
Immune Cell ◽  
Critical Role ◽  
Cellular Polarity ◽  
Endothelial Layer ◽  
Trichoplax Adhaerens ◽  
Migration Pathway ◽  
Two Systems ◽  
Sequence Reconstruction ◽  
Rhoa Protein ◽  
Migration Pathways

Infiltration of the endothelial layer of the blood-brain barrier by leukocytes plays a critical role in health and disease. When passing through the endothelial layer during the diapedesis process lymphocytes can either follow a paracellular route or a transcellular one. There is a debate whether these two processes constitute one mechanism, or they form two evolutionary distinct migration pathways. We used artificial intelligence, phylogenetic analysis, HH search, ancestor sequence reconstruction to investigate further this intriguing question. We found that the two systems share several ancient components, such as RhoA protein that plays a critical role in controlling actin movement in both mechanisms. However, some of the key components differ between these two transmigration processes. CAV1 genes emerged during Trichoplax adhaerens, and it was only reported in transcellular process. Paracellular process is dependent on PECAM1. PECAM1 emerged from FASL5 during Zebrafish divergence. Lastly, both systems employ late divergent genes such as ICAM1 and VECAM1. Taken together, our results suggest that these two systems constitute two different mechanical sensing mechanisms of immune cell infiltrations of the brain, yet these two systems are connected. We postulate that the mechanical properties of the cellular polarity is the main driving force determining the migration pathway. Our analysis indicates that both systems coevolved with immune cells, evolving to a higher level of complexity in association with the evolution of the immune system.

Genetic and Epigenetic landscape of leukocyte infiltration identifies an immune prognosticator in lung adenocarcinoma

2021 ◽  
pp. 1-13
Author(s):  
Seema Khadirnaikar ◽  
Annesha Chatterjee ◽  
Sudhanshu Kumar Shukla
Keyword(s):  
Lung Adenocarcinoma ◽  
Immune Cell ◽  
Cox Regression ◽  
Strong Association ◽  
Critical Role ◽  
Significant Proportion ◽  
Immune Gene ◽  
Leukocyte Infiltration ◽  
Clinical Genetic ◽  
Factors Affecting

BACKGROUND: Leukocyte infiltration plays an critical role in outcome of various diseases including Lung adenocarcinoma (LUAD). OBJECTIVES: To understand the genetic and epigenetic factors affecting leukocyte infiltration and identification and validation of immune based biomarkers. METHOD: Correlation analysis was done to get the associations of the factors. CIBERSORT analysis was done for immune cell infiltration. Genetic and epigenetic analysis were performed. Cox regression was carried out for survival. RESULTS: We categorized the TCGA-LUAD patients based on Leukocyte fraction (LF) and performed extensive immunogenomic analysis. Interestingly, we showed that LF has a negative correlation with copy number variation (CNV) but not with mutational load. However, several individual genetic mutations, including KRAS and KEAP1, were significantly linked with LF. Also, as expected, patients with high LF showed significantly increased expression of genes involved in leukocyte migration and activation. DNA methylation changes also showed a strong association with LF and regulated a significant proportion of genes associated with LF. We also developed and validated an independent prognostic immune signature using the top six prognostic genes associated with LF. CONCLUSION: Together, we have identified clinical, genetic, and epigenetic variations associated with LUAD LF and developed an immune gene-based signature for disease prognostication.

scholarly journals RhoA Signaling in Immune Cell Response and Cardiac Disease

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1681
Author(s):  
Lucia Sophie Kilian ◽  
Derk Frank ◽  
Ashraf Yusuf Rangrez
Keyword(s):  
Cardiac Disease ◽  
Cell Response ◽  
Cell Activation ◽  
Immune Cell ◽  
Inflammatory Diseases ◽  
Heart Diseases ◽  
Small Gtpase ◽  
Cardiac Inflammation ◽  
Immune Cell Activation ◽  
Immune Cell Response

Chronic inflammation, the activation of immune cells and their cross-talk with cardiomyocytes in the pathogenesis and progression of heart diseases has long been overlooked. However, with the latest research developments, it is increasingly accepted that a vicious cycle exists where cardiomyocytes release cardiocrine signaling molecules that spiral down to immune cell activation and chronic state of low-level inflammation. For example, cardiocrine molecules released from injured or stressed cardiomyocytes can stimulate macrophages, dendritic cells, neutrophils and even T-cells, which then subsequently increase cardiac inflammation by co-stimulation and positive feedback loops. One of the key proteins involved in stress-mediated cardiomyocyte signal transduction is a small GTPase RhoA. Importantly, the regulation of RhoA activation is critical for effective immune cell response and is being considered as one of the potential therapeutic targets in many immune-cell-mediated inflammatory diseases. In this review we provide an update on the role of RhoA at the juncture of immune cell activation, inflammation and cardiac disease.

scholarly journals Expression and function of Smad7 in autoimmune and inflammatory diseases

2021 ◽  
Author(s):  
Yiping Hu ◽  
Juan He ◽  
Lianhua He ◽  
Bihua Xu ◽  
Qingwen Wang
Keyword(s):  
Posttranscriptional Regulation ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Inflammatory Diseases ◽  
Kidney Diseases ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Signaling Mechanism ◽  
And Function

AbstractTransforming growth factor-β (TGF-β) plays a critical role in the pathological processes of various diseases. However, the signaling mechanism of TGF-β in the pathological response remains largely unclear. In this review, we discuss advances in research of Smad7, a member of the I-Smads family and a negative regulator of TGF-β signaling, and mainly review the expression and its function in diseases. Smad7 inhibits the activation of the NF-κB and TGF-β signaling pathways and plays a pivotal role in the prevention and treatment of various diseases. Specifically, Smad7 can not only attenuate growth inhibition, fibrosis, apoptosis, inflammation, and inflammatory T cell differentiation, but also promotes epithelial cells migration or disease development. In this review, we aim to summarize the various biological functions of Smad7 in autoimmune diseases, inflammatory diseases, cancers, and kidney diseases, focusing on the molecular mechanisms of the transcriptional and posttranscriptional regulation of Smad7.

scholarly journals Novel Insights into YB-1 Signaling and Cell Death Decisions

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3306
Author(s):  
Aneri Shah ◽  
Jonathan A. Lindquist ◽  
Lars Rosendahl ◽  
Ingo Schmitz ◽  
Peter R. Mertens
Keyword(s):  
Stress Responses ◽  
Rna Splicing ◽  
Cell Cycle Progression ◽  
Rna Binding ◽  
Inflammatory Responses ◽  
Rna Binding Proteins ◽  
Inflammatory Diseases ◽  
Therapeutic Option ◽  
Tumor Therapy ◽  
Inflammatory Microenvironment

YB-1 belongs to the evolutionarily conserved cold-shock domain protein family of RNA binding proteins. YB-1 is a well-known transcriptional and translational regulator, involved in cell cycle progression, DNA damage repair, RNA splicing, and stress responses. Cell stress occurs in many forms, e.g., radiation, hyperthermia, lipopolysaccharide (LPS) produced by bacteria, and interferons released in response to viral infection. Binding of the latter factors to their receptors induces kinase activation, which results in the phosphorylation of YB-1. These pathways also activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a well-known transcription factor. NF-κB is upregulated following cellular stress and orchestrates inflammatory responses, cell proliferation, and differentiation. Inflammation and cancer are known to share common mechanisms, such as the recruitment of infiltrating macrophages and development of an inflammatory microenvironment. Several recent papers elaborate the role of YB-1 in activating NF-κB and signaling cell survival. Depleting YB-1 may tip the balance from survival to enhanced apoptosis. Therefore, strategies that target YB-1 might be a viable therapeutic option to treat inflammatory diseases and improve tumor therapy.

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