scholarly journals Harnessing the Activation of RIG-I Like Receptors to Inhibit Glioblastoma Tumorigenesis

2021 ◽  
Vol 14 ◽  
Author(s):  
Francesca Bufalieri ◽  
Irene Basili ◽  
Lucia Di Marcotullio ◽  
Paola Infante
Keyword(s):  
Tumor Antigens ◽  
Standard Of Care ◽  
Innate Immune ◽  
Molecular Heterogeneity ◽  
Type I ◽  
Current Standard ◽  
Adaptive Immune ◽  
Wide Range ◽  
Anti Cancer ◽  
Immunosuppressive Microenvironment

Glioblastoma (GB) is an incurable form of brain malignancy in an adult with a median survival of less than 15 months. The current standard of care, which consists of surgical resection, radiotherapy, and chemotherapy with temozolomide, has been unsuccessful due to an extensive inter- and intra-tumoral genetic and molecular heterogeneity. This aspect represents a serious obstacle for developing alternative therapeutic options for GB. In the last years, immunotherapy has emerged as an effective treatment for a wide range of cancers and several trials have evaluated its effects in GB patients. Unfortunately, clinical outcomes were disappointing particularly because of the presence of tumor immunosuppressive microenvironment. Recently, anti-cancer approaches aimed to improve the expression and the activity of RIG-I-like receptors (RLRs) have emerged. These innovative therapeutic strategies attempt to stimulate both innate and adaptive immune responses against tumor antigens and to promote the apoptosis of cancer cells. Indeed, RLRs are important mediators of the innate immune system by triggering the type I interferon (IFN) response upon recognition of immunostimulatory RNAs. In this mini-review, we discuss the functions of RLRs family members in the control of immune response and we focus on the potential clinical application of RLRs agonists as a promising strategy for GB therapy.

scholarly journals Role of the Innate Immunity Signaling Pathway in the Pathogenesis of Sjögren’s Syndrome

2021 ◽  
Vol 22 (6) ◽  
pp. 3090
Author(s):  
Toshimasa Shimizu ◽  
Hideki Nakamura ◽  
Atsushi Kawakami
Keyword(s):  
Immune Responses ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Innate Immune ◽  
Type I ◽  
Type I Ifn ◽  
Adaptive Immune ◽  
Sjögren‘S Syndrome

Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by chronic inflammation of the salivary and lacrimal glands and extra-glandular lesions. Adaptive immune response including T- and B-cell activation contributes to the development of SS. However, its pathogenesis has not yet been elucidated. In addition, several patients with SS present with the type I interferon (IFN) signature, which is the upregulation of the IFN-stimulated genes induced by type I IFN. Thus, innate immune responses including type I IFN activity are associated with SS pathogenesis. Recent studies have revealed the presence of activation pattern recognition receptors (PRRs) including Toll-like receptors, RNA sensor retinoic acid-inducible gene I and melanoma differentiation-associated gene 5, and inflammasomes in infiltrating and epithelial cells of the salivary glands among patients with SS. In addition, the activation of PRRs via the downstream pathway such as the type I IFN signature and nuclear factor kappa B can directly cause organ inflammation, and it is correlated with the activation of adaptive immune responses. Therefore, this study assessed the role of the innate immune signal pathway in the development of inflammation and immune abnormalities in SS.

scholarly journals RNA N6-Methyladenosine Modifications and the Immune Response

2020 ◽  
Vol 2020 ◽  
pp. 1-6 ◽  
Author(s):  
Ya-Nan Wang ◽  
Chen-Yang Yu ◽  
Hong-Zhong Jin
Keyword(s):  
Immune Response ◽  
Biological Effects ◽  
Biological Significance ◽  
Adaptive Immune Response ◽  
Noncoding Rnas ◽  
Innate Immune ◽  
Messenger Rnas ◽  
Adaptive Immune ◽  
Wide Range ◽  
Higher Eukaryotes

N6-methyladenosine (m6A) is the most important modification of messenger RNAs (mRNAs) and long noncoding RNAs (lncRNAs) in higher eukaryotes. Modulation of m6A modifications relies on methyltransferases and demethylases. The discovery of binding proteins confirms that the m6A modification has a wide range of biological effects and significance at the molecular, cellular, and physiological levels. In recent years, techniques for investigating m6A modifications of RNA have developed rapidly. This article reviews the biological significance of RNA m6A modifications in the innate immune response, adaptive immune response, and viral infection.

The innate immune system in human systemic lupus erythematosus

2017 ◽  
Vol 131 (8) ◽  
pp. 625-634 ◽  
Author(s):  
Marc Weidenbusch ◽  
Onkar P. Kulkarni ◽  
Hans-Joachim Anders
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Immune System ◽  
Lupus Erythematosus ◽  
Innate Immune System ◽  
Innate Immune ◽  
Type I ◽  
Human Systemic Lupus Erythematosus ◽  
Systemic Lupus ◽  
Adaptive Immune

Although the role of adaptive immune mechanisms, e.g. autoantibody formation and abnormal T-cell activation, has been long noted in the pathogenesis of human systemic lupus erythematosus (SLE), the role of innate immunity has been less well characterized. An intricate interplay between both innate and adaptive immune elements exists in protective anti-infective immunity as well as in detrimental autoimmunity. More recently, it has become clear that the innate immune system in this regard not only starts inflammation cascades in SLE leading to disease flares, but also continues to fuel adaptive immune responses throughout the course of the disease. This is why targeting the innate immune system offers an additional means of treating SLE. First trials assessing the efficacy of anti-type I interferon (IFN) therapy or modulators of pattern recognition receptor (PRR) signalling have been attempted. In this review, we summarize the available evidence on the role of several distinct innate immune elements, especially neutrophils and dendritic cells as well as the IFN system, as well as specific innate PRRs along with their signalling pathways. Finally, we highlight recent clinical trials in SLE addressing one or more of the aforementioned components of the innate immune system.

scholarly journals Roles of Inflammasome in Cigarette Smoke-Related Diseases and Physiopathological Disorders: Mechanisms and Therapeutic Opportunities

2021 ◽  
Vol 12 ◽  
Author(s):  
Yiming Ma ◽  
Yingjiao Long ◽  
Yan Chen
Keyword(s):  
Cigarette Smoke ◽  
Kidney Injury ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Therapeutic Effects ◽  
Barrier Dysfunction ◽  
Podocyte Injury ◽  
Adaptive Immune ◽  
Wide Range ◽  
Macrophage Dysfunction

Cigarette smoke damages a wide range of immunological functions, including innate and adaptive immune responses. Emerging literature demonstrates that inflammasome constitutes an essential component in innate immune response. In this review, we focus on the cumulative mechanisms of inflammasome in cigarette smoke-related diseases and physiopathological disorders, and summarize potential therapeutic opportunities targeting inflammasome. This review suggests that inflammasomes (NLRP3, NLRP6, NLRP12 and AIM2) are involved in the pathogenesis of several cigarette smoke-related diseases (including COPD, ALI, atherosclerosis, kidney injury, bladder dysfunction, and oral leukoplakia) and physiopathological disorders (macrophage dysfunction, endothelial barrier dysfunction, podocyte injury, and ubiquitin-mediated proteasomal processing). MyD88/NF-κB, HMGB1, production of ROS, endoplasmic reticulum stress and mitochondrial dysfunction, and Ca2+ influx are potentially involved in cigarette smoke induced-inflammasome activation. Strategies targeting ROS/NLRP3 inflammasome axis are most widely investigated and show potential therapeutic effects.

scholarly journals Innate immune signatures to a partially-efficacious HIV vaccine predict correlates of HIV-1 infection risk

2021 ◽  
Vol 17 (3) ◽  
pp. e1009363
Author(s):  
Erica Andersen-Nissen ◽  
Andrew Fiore-Gartland ◽  
Lamar Ballweber Fleming ◽  
Lindsay N. Carpp ◽  
Anneta F. Naidoo ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Responses ◽  
Innate Immune ◽  
Cd4 T Cell ◽  
Type I ◽  
Transcriptional Responses ◽  
Cell Responses ◽  
Adaptive Immune ◽  
Immune Biomarkers ◽  
Hiv 1

The pox-protein regimen tested in the RV144 trial is the only vaccine strategy demonstrated to prevent HIV-1 infection. Subsequent analyses identified antibody and cellular immune responses as correlates of risk (CoRs) for HIV infection. Early predictors of these CoRs could provide insight into vaccine-induced protection and guide efforts to enhance vaccine efficacy. Using specimens from a phase 1b trial of the RV144 regimen in HIV-1-uninfected South Africans (HVTN 097), we profiled innate responses to the first ALVAC-HIV immunization. PBMC transcriptional responses peaked 1 day post-vaccination. Type I and II interferon signaling pathways were activated, as were innate pathways critical for adaptive immune priming. We then identified two innate immune transcriptional signatures strongly associated with adaptive immune CoR after completion of the 4-dose regimen. Day 1 signatures were positively associated with antibody-dependent cellular cytotoxicity and phagocytosis activity at Month 6.5. Conversely, a signature present on Days 3 and 7 was inversely associated with Env-specific CD4+ T cell responses at Months 6.5 and 12; rapid resolution of this signature was associated with higher Env-specific CD4+ T-cell responses. These are the first-reported early immune biomarkers of vaccine-induced responses associated with HIV-1 acquisition risk in humans and suggest hypotheses to improve HIV-1 vaccine regimens.

scholarly journals Bromodomain protein Brd3 promotes Ifnb1 transcription via enhancing IRF3/p300 complex formation and recruitment to Ifnb1 promoter in macrophages

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Wenhui Ren ◽  
Chunmei Wang ◽  
Qinlan Wang ◽  
Dezhi Zhao ◽  
Kai Zhao ◽  
...  
Keyword(s):  
Immune Response ◽  
Virus Infection ◽  
Innate Immune Response ◽  
Transcriptional Activation ◽  
Cell Cycle Progression ◽  
Innate Immune ◽  
Type I ◽  
Wide Range ◽  
Bromodomain Proteins ◽  
Protein Scaffolding

AbstractAs members of bromodomain and extra-terminal motif protein family, bromodomain-containing proteins regulate a wide range of biological processes including protein scaffolding, mitosis, cell cycle progression and transcriptional regulation. The function of these bromodomain proteins (Brds) in innate immune response has been reported but the role of Brd3 remains unclear. Here we find that virus infection significantly downregulate Brd3 expression in macrophages and Brd3 knockout inhibits virus-triggered IFN-β production. Brd3 interacts with both IRF3 and p300, increases p300-mediated acetylation of IRF3, and enhances the association of IRF3 with p300 upon virus infection. Importantly, Brd3 promotes the recruitment of IRF3/p300 complex to the promoter of Ifnb1, and increases the acetylation of histone3/histone4 within the Ifnb1 promoter, leading to the enhancement of type I interferon production. Therefore, our work indicated that Brd3 may act as a coactivator in IRF3/p300 transcriptional activation of Ifnb1 and provided new epigenetic mechanistic insight into the efficient activation of the innate immune response.

PRRs in pathogen recognition

2006 ◽  
Vol 1 (3) ◽  
pp. 299-313 ◽  
Author(s):  
Satoshi Uematsu ◽  
Shizuo Akira
Keyword(s):  
Pattern Recognition ◽  
Immune Responses ◽  
Pattern Recognition Receptors ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Pathogen Recognition ◽  
First Line ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Wide Range

AbstractThe innate immune system provides the first line of host defense against invading microorganisms before the development of adaptive immune responses. Innate immune responses are initiated by germline-encoded pattern recognition receptors (PRRs), which recognize specific structures of microorganisms. Toll-like receptors (TLRs) are pattern-recognition receptors that sense a wide range of microorganisms, including bacteria, fungi, protozoa and viruses. TLRs exist either on the cell surface or in the lysosome/endosome compartment and induce innate immune responses. Recently, cytoplasmic PRRs have been identified which detect pathogens that have invaded the cytosol. This review focuses on the pathogen recognition of PRRs in innate immunity.

scholarly journals Tweaking Innate Immunity: The Promise of Innate Immunologicals as Anti-Infectives

2006 ◽  
Vol 17 (5) ◽  
pp. 307-314 ◽  
Author(s):  
Kenneth L Rosenthal
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Immune Responses ◽  
Innate Immune System ◽  
Immune Defense ◽  
Innate Immune ◽  
Parasitic Infections ◽  
Type I ◽  
Adaptive Immune Responses ◽  
Adaptive Immune

New and exciting insights into the importance of the innate immune system are revolutionizing our understanding of immune defense against infections, pathogenesis, and the treatment and prevention of infectious diseases. The innate immune system uses multiple families of germline-encoded pattern recognition receptors (PRRs) to detect infection and trigger a variety of antimicrobial defense mechanisms. PRRs are evolutionarily highly conserved and serve to detect infection by recognizing pathogen-associated molecular patterns that are unique to microorganisms and essential for their survival. Toll-like receptors (TLRs) are transmembrane signalling receptors that activate gene expression programs that result in the production of proinflammatory cytokines and chemokines, type I interferons and antimicrobial factors. Furthermore, TLR activation facilitates and guides activation of adaptive immune responses through the activation of dendritic cells. TLRs are localized on the cell surface and in endosomal/lysosomal compartments, where they detect bacterial and viral infections. In contrast, nucleotide-binding oligomerization domain proteins and RNA helicases are located in the cell cytoplasm, where they serve as intracellular PRRs to detect cytoplasmic infections, particularly viruses. Due to their ability to enhance innate immune responses, novel strategies to use ligands, synthetic agonists or antagonists of PRRs (also known as 'innate immunologicals') can be used as stand-alone agents to provide immediate protection or treatment against bacterial, viral or parasitic infections. Furthermore, the newly appreciated importance of innate immunity in initiating and shaping adaptive immune responses is contributing to our understanding of vaccine adjuvants and promises to lead to improved next-generation vaccines.

scholarly journals Glioblastoma’s Next Top Model: Novel Culture Systems for Brain Cancer Radiotherapy Research

Cancers ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 44 ◽  
Author(s):  
Seamus Caragher ◽  
Anthony J. Chalmers ◽  
Natividad Gomez-Roman
Keyword(s):  
Mouse Models ◽  
Standard Of Care ◽  
Primary Brain Tumor ◽  
Current Standard ◽  
Meaningful Improvement ◽  
Nutrient Sources ◽  
Culture Systems ◽  
Novel Treatments ◽  
Wide Range

Glioblastoma (GBM), the most common and aggressive primary brain tumor in adults, remains one of the least treatable cancers. Current standard of care—combining surgical resection, radiation, and alkylating chemotherapy—results in a median survival of only 15 months. Despite decades of investment and research into the development of new therapies, most candidate anti-glioma compounds fail to translate into effective treatments in clinical trials. One key issue underlying this failure of therapies that work in pre-clinical models to generate meaningful improvement in human patients is the profound mismatch between drug discovery systems—cell cultures and mouse models—and the actual tumors they are supposed to imitate. Indeed, current strategies that evaluate the effects of novel treatments on GBM cells in vitro fail to account for a wide range of factors known to influence tumor growth. These include secreted factors, the brain’s unique extracellular matrix, circulatory structures, the presence of non-tumor brain cells, and nutrient sources available for tumor metabolism. While mouse models provide a more realistic testing ground for potential therapies, they still fail to account for the full complexity of tumor-microenvironment interactions, as well as the role of the immune system. Based on the limitations of current models, researchers have begun to develop and implement novel culture systems that better recapitulate the complex reality of brain tumors growing in situ. A rise in the use of patient derived cells, creative combinations of added growth factors and supplements, may provide a more effective proving ground for the development of novel therapies. This review will summarize and analyze these exciting developments in 3D culturing systems. Special attention will be paid to how they enhance the design and identification of compounds that increase the efficacy of radiotherapy, a bedrock of GBM treatment.

scholarly journals 2608. Restriction of Rhinovirus Infection Depends on Virus Sensing and Early IFN Induction

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S907-S907
Author(s):  
Jennifer A Rathe ◽  
Michael Gale Jr. ◽  
Megan Knoll
Keyword(s):  
Post Infection ◽  
Acute Infection ◽  
Innate Immune ◽  
Epithelial Cell Line ◽  
Type I ◽  
Dependent Manner ◽  
Epithelial Surface ◽  
Immune Defenses ◽  
Wide Range ◽  
Viral Titers

Abstract Background Human rhinovirus (RV) infections are ubiquitous, underestimated, and costly. RV causes 3–12 infections per year per individual with a wide range of clinical presentations from mild upper respiratory infections to severe viral pneumonias (1). The virus-host interactions that control RV infection are poorly understood. Thus, there are no vaccines or antiviral medications available. RV infection begins at the airway epithelial surface where the virus first encounters the host cell immune defenses, including type I and III interferon (IFN). IFN actions are critical for defense against RV infection wherein interferon-stimulated genes (ISG)s direct antiviral actions to limit RV infection. Methods We hypothesized that the timing of IFN induction is a critical determinant of RV restriction by host innate immune defenses in the human respiratory tract. Thus, an immortalized bronchial epithelial cell line was infected with RV-14 with multiplicity of infection (MOI) ranging from 0.1 – 10 and under conditions of pre/post infection treatment with IFN-β or IFN-λ. Host and viral RNA, protein, and RV infectious particle levels were analyzed. Results We found that RV infection induces IFN-β and IFN-λ production and subsequent ISG induction, including expression of IFIT-1, OAS1, and MX1. RV-14 infection induced IFN-β and IFN-λ in a dose-dependent manner, with a maximum fold increase of IFN expression at 48hours post infection. ISGs were induced in a similar pattern to IFNs. Viral titers increased significantly over the first 24hours post infection and then plateaued through 96hours. IFN-β and IFN-λ pre- and posttreatment conditions significantly decreased maximum viral titers achieved but with continued viral plateaus 24–96 hours post infection. Conclusion Our observations demonstrate that RV induces innate immune activation and the production of type I and III IFN during acute infection of airway cells. Sustained viral titer plateaus, despite antiviral ISG induction, suggests viral blocking of IFN pathway mechanisms that can be overcome by early IFN induction to significantly restrict RV viral replication. 1. Royston L, Tapparel C. 2016. Rhinoviruses and Respiratory Enteroviruses: Not as Simple as ABC. Viruses 8. Disclosures All authors: No reported disclosures.

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