Stimulator of Interferon Genes Signaling Pathway and its Role in Anti-tumor Immune Therapy

2020 ◽  
Vol 26 (26) ◽  
pp. 3085-3095 ◽  
Author(s):  
Yuanjin Gong ◽  
Chang Chang ◽  
Xi Liu ◽  
Yan He ◽  
Yiqi Wu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Immune Therapy ◽  
Signal Transduction Pathway ◽  
The Body ◽  
Innate Immune ◽  
Type I ◽  
Innate Immune Signaling ◽  
Critical Problems ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Stimulator of interferon genes is an important innate immune signaling molecule in the body and is involved in the innate immune signal transduction pathway induced by pathogen-associated molecular patterns or damage-associated molecular patterns. Stimulator of interferon genes promotes the production of type I interferon and thus plays an important role in the innate immune response to infection. In addition, according to a recent study, the stimulator of interferon genes pathway also contributes to anti-inflammatory and anti-tumor reactions. In this paper, current researches on the Stimulator of interferon genes signaling pathway and its relationship with tumor immunity are reviewed. Meanwhile, a series of critical problems to be addressed in subsequent studies are discussed as well.

scholarly journals Innate immunology in COVID-19—a living review. Part II: dysregulated inflammation drives immunopathology

2020 ◽  
Vol 1 (1) ◽  
Author(s):  
Patrícia R S Rodrigues ◽  
Aljawharah Alrubayyi ◽  
Ellie Pring ◽  
Valentina M T Bart ◽  
Ruth Jones ◽  
...  
Keyword(s):  
Immune Responses ◽  
Current Knowledge ◽  
Innate Immune ◽  
Type I ◽  
Innate Immune Responses ◽  
Innate Immunology ◽  
Viral Pathogen ◽  
Health Crisis ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Abstract The current pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a global health crisis and will likely continue to impact public health for years. As the effectiveness of the innate immune response is crucial to patient outcome, huge efforts have been made to understand how dysregulated immune responses may contribute to disease progression. Here we have reviewed current knowledge of cellular innate immune responses to SARS-CoV-2 infection, highlighting areas for further investigation and suggesting potential strategies for intervention. We conclude that in severe COVID-19 initial innate responses, primarily type I interferon, are suppressed or sabotaged which results in an early interleukin (IL)-6, IL-10 and IL-1β-enhanced hyperinflammation. This inflammatory environment is driven by aberrant function of innate immune cells: monocytes, macrophages and natural killer cells dispersing viral pathogen-associated molecular patterns and damage-associated molecular patterns into tissues. This results in primarily neutrophil-driven pathology including fibrosis that causes acute respiratory distress syndrome. Activated leukocytes and neutrophil extracellular traps also promote immunothrombotic clots that embed into the lungs and kidneys of severe COVID-19 patients, are worsened by immobility in the intensive care unit and are perhaps responsible for the high mortality. Therefore, treatments that target inflammation and coagulation are promising strategies for reducing mortality in COVID-19.

scholarly journals Molecular biology of autoinflammatory diseases

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
Junya Masumoto ◽  
Wei Zhou ◽  
Shinnosuke Morikawa ◽  
Sho Hosokawa ◽  
Haruka Taguchi ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cell Injury ◽  
Innate Immune ◽  
Autoinflammatory Diseases ◽  
Type I ◽  
Adaptive Responses ◽  
Autoinflammatory Syndromes ◽  
Physical Chemical ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

AbstractThe long battle between humans and various physical, chemical, and biological insults that cause cell injury (e.g., products of tissue damage, metabolites, and/or infections) have led to the evolution of various adaptive responses. These responses are triggered by recognition of damage-associated molecular patterns (DAMPs) and/or pathogen-associated molecular patterns (PAMPs), usually by cells of the innate immune system. DAMPs and PAMPs are recognized by pattern recognition receptors (PRRs) expressed by innate immune cells; this recognition triggers inflammation. Autoinflammatory diseases are strongly associated with dysregulation of PRR interactomes, which include inflammasomes, NF-κB-activating signalosomes, type I interferon-inducing signalosomes, and immuno-proteasome; disruptions of regulation of these interactomes leads to inflammasomopathies, relopathies, interferonopathies, and proteasome-associated autoinflammatory syndromes, respectively. In this review, we discuss the currently accepted molecular mechanisms underlying several autoinflammatory diseases.

scholarly journals The Role of LAMP5 in Innate Immune Signaling Is Critical for the Survival of MLL Leukemias

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3900-3900
Author(s):  
Gabriel Gracia-Maldonado ◽  
Jason Clark ◽  
Philippe Pierre ◽  
James C. Mulloy ◽  
Ashish R Kumar
Keyword(s):  
Signaling Pathway ◽  
Leukemia Cell ◽  
Innate Immune ◽  
Leukemia Cell Line ◽  
Therapeutic Window ◽  
Type I ◽  
Tlr Signaling ◽  
Immune Signaling ◽  
Over Expression ◽  
Innate Immune Signaling

Abstract Introduction Chromosomal translocations involving the Mixed Lineage Leukemia (MLL, also called KMT2A) gene account for around 80% of the acute lymphoid leukemia (ALL) and 35%-50% of the acute myeloid leukemia (AML) diagnosed in infants, and are associated with poor outcomes. Despite improvements of conventional chemotherapies and treatments, patients with MLL-rearranged leukemia have weak response to treatment and poor prognosis. There is thus an urgent need to understand the molecular pathogenesis of these leukemias to develop more effective therapies. Gene expression studies show that MLL-leukemias uniquely display over-expression of Lysosome-associated Membrane Protein 5 (LAMP5) in both ALL and AML In normal hematopoiesis, LAMP5 expression is restricted to non-activated plasmacytoid dendritic cells (pDC), where it has been shown to be required for transport of TLR9 from VAMP3+/LAMP2+/LAMP1- endolysosomal vesicles to the LAMP1+ late lysosomal compartments, modulating the signaling and production of Type I interferon to TNF production. Here, we tested the hypothesis that LAMP5 is required for MLL leukemia wherein it modulates innate immune signaling. Methods and Results In previous studies, we found LAMP5 expression being restricted to MLL-fusion leukemia cell lines. Additionally, in an inducible model, LAMP5 expression directly correlated with that of the MLL-fusion protein MLL-AF9. . Knockdown on LAMP5 in MLL-fusion leukemia cells inhibited their propagation both in vitro and in vivo whereas the non-MLL leukemias were unaffected. To determine the mechanisms by which LAMP5 promotes growth in MLL leukemias, first we studied the localization of LAMP5 in these cells. Using immunofluorescent confocal microscopy we detected LAMP5 mainly in LAMP2+/LAMP1+ compartments. Additionally, LAMP5 co-localized with MYD88, a known scaffold protein required for IL1R/TLR signaling. Accordingly, LAMP5-knockdown abrogated TLR signaling as evidenced by reduced activation of JNK, MAPK p38, IRF7 and NFKB. Conversely, over-expression of LAMP5 in the non-MLL leukemia cell line Kasumi-1 led to increased activation of JNK, p38, IRF7 and NFKB, indicating that the innate-immune signaling pathway is regulated by LAMP5 expression in leukemias.r Conclusions Collectively, these results demonstrate that LAMP5 is required for the survival of MLL leukemia and that it plays an important role in the activation of the IL1/TLR signaling pathway. Overall, based on our results and the limited expression in normal hematopoiesis, we propose that LAMP5 could potentially serve as a therapeutic target with a wide therapeutic-window to treat MLL-leukemias. Disclosures No relevant conflicts of interest to declare.

scholarly journals Two Sides of the Coin: Mast Cells as a Key Regulator of Allergy and Acute/Chronic Inflammation

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1615
Author(s):  
Zhongwei Zhang ◽  
Yosuke Kurashima
Keyword(s):  
Mast Cells ◽  
Chronic Inflammation ◽  
Regulatory Function ◽  
Type I ◽  
Allergic Reactions ◽  
Novel Approach ◽  
Molecular Patterns ◽  
Regulatory Functions ◽  
Damage Associated Molecular Patterns ◽  
Two Sides

It is well known that mast cells (MCs) initiate type I allergic reactions and inflammation in a quick response to the various stimulants, including—but not limited to—allergens, pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs). MCs highly express receptors of these ligands and proteases (e.g., tryptase, chymase) and cytokines (TNF), and other granular components (e.g., histamine and serotonin) and aggravate the allergic reaction and inflammation. On the other hand, accumulated evidence has revealed that MCs also possess immune-regulatory functions, suppressing chronic inflammation and allergic reactions on some occasions. IL-2 and IL-10 released from MCs inhibit excessive immune responses. Recently, it has been revealed that allergen immunotherapy modulates the function of MCs from their allergic function to their regulatory function to suppress allergic reactions. This evidence suggests the possibility that manipulation of MCs functions will result in a novel approach to the treatment of various MCs-mediated diseases.

scholarly journals Biomarkers of Radiotherapy-Induced Immunogenic Cell Death

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 930
Author(s):  
Rianne D. W. Vaes ◽  
Lizza E. L. Hendriks ◽  
Marc Vooijs ◽  
Dirk De Ruysscher
Keyword(s):  
Cell Death ◽  
Immune Responses ◽  
Tumor Cells ◽  
Immunogenic Cell Death ◽  
Type I ◽  
Future Studies ◽  
Regulated Cell Death ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Potential Biomarkers

Radiation therapy (RT) can induce an immunogenic variant of regulated cell death that can initiate clinically relevant tumor-targeting immune responses. Immunogenic cell death (ICD) is accompanied by the exposure and release of damage-associated molecular patterns (DAMPs), chemokine release, and stimulation of type I interferon (IFN-I) responses. In recent years, intensive research has unraveled major mechanistic aspects of RT-induced ICD and has resulted in the identification of immunogenic factors that are released by irradiated tumor cells. However, so far, only a limited number of studies have searched for potential biomarkers that can be used to predict if irradiated tumor cells undergo ICD that can elicit an effective immunogenic anti-tumor response. In this article, we summarize the available literature on potential biomarkers of RT-induced ICD that have been evaluated in cancer patients. Additionally, we discuss the clinical relevance of these findings and important aspects that should be considered in future studies.

scholarly journals Hepatitis C Virus Infection Is Inhibited by a Noncanonical Antiviral Signaling Pathway Targeted by NS3-NS4A

2019 ◽  
Vol 93 (23) ◽  
Author(s):  
Christine Vazquez ◽  
Chin Yee Tan ◽  
Stacy M. Horner
Keyword(s):  
Hepatitis C ◽  
Viral Replication ◽  
Signaling Pathway ◽  
Transmembrane Domain ◽  
Innate Immune ◽  
Hcv Infection ◽  
Interferon Induction ◽  
Innate Immune Signaling ◽  
Huh7 Cells ◽  
Irf3 Activation

ABSTRACT The hepatitis C virus (HCV) NS3-NS4A protease complex is required for viral replication and is the major viral innate immune evasion factor. NS3-NS4A evades antiviral innate immunity by inactivating several proteins, including MAVS, the signaling adaptor for RIG-I and MDA5, and Riplet, an E3 ubiquitin ligase that activates RIG-I. Here, we identified a Tyr-16-Phe (Y16F) change in the NS4A transmembrane domain that prevents NS3-NS4A targeting of Riplet but not MAVS. This Y16F substitution reduces HCV replication in Huh7 cells, but not in Huh-7.5 cells, known to lack RIG-I signaling. Surprisingly, deletion of RIG-I in Huh7 cells did not restore Y16F viral replication. Rather, we found that Huh-7.5 cells lack Riplet expression and that the addition of Riplet to these cells reduced HCV Y16F replication, whereas the addition of Riplet lacking the RING domain restored HCV Y16F replication. In addition, TBK1 inhibition or IRF3 deletion in Huh7 cells was sufficient to restore HCV Y16F replication, and the Y16F protease lacked the ability to prevent IRF3 activation or interferon induction. Taken together, these data reveal that the NS4A Y16 residue regulates a noncanonical Riplet-TBK1-IRF3-dependent, but RIG-I-MAVS-independent, signaling pathway that limits HCV infection. IMPORTANCE The HCV NS3-NS4A protease complex facilitates viral replication by cleaving and inactivating the antiviral innate immune signaling proteins MAVS and Riplet, which are essential for RIG-I activation. NS3-NS4A therefore prevents IRF3 activation and interferon induction during HCV infection. Here, we uncover an amino acid residue within the NS4A transmembrane domain that is essential for inactivation of Riplet but does not affect MAVS cleavage by NS3-NS4A. Our study reveals that Riplet is involved in a RIG-I- and MAVS-independent signaling pathway that activates IRF3 and that this pathway is normally inactivated by NS3-NS4A during HCV infection. Our study selectively uncouples these distinct regulatory mechanisms within NS3-NS4A and defines a new role for Riplet in the antiviral response to HCV. Since Riplet is known to be inhibited by other RNA viruses, such as such influenza A virus, this innate immune signaling pathway may also be important in controlling other RNA virus infections.

scholarly journals MAVS: A Two-Sided CARD Mediating Antiviral Innate Immune Signaling and Regulating Immune Homeostasis

2021 ◽  
Vol 12 ◽  
Author(s):  
Yunqiang Chen ◽  
Yuheng Shi ◽  
Jing Wu ◽  
Nan Qi
Keyword(s):  
Signal Transduction ◽  
Innate Immune ◽  
Immune Homeostasis ◽  
Type I ◽  
Interferon Signaling ◽  
Immune Signaling ◽  
Post Translational Modifications ◽  
Innate Immune Signaling ◽  
Mitochondrial Antiviral Signaling ◽  
Mitochondrial Antiviral Signaling Protein

Mitochondrial antiviral signaling protein (MAVS) functions as a “switch” in the immune signal transduction against most RNA viruses. Upon viral infection, MAVS forms prion-like aggregates by receiving the cytosolic RNA sensor retinoic acid-inducible gene I-activated signaling and further activates/switches on the type I interferon signaling. While under resting state, MAVS is prevented from spontaneously aggregating to switch off the signal transduction and maintain immune homeostasis. Due to the dual role in antiviral signal transduction and immune homeostasis, MAVS has emerged as the central regulation target by both viruses and hosts. Recently, researchers show increasing interest in viral evasion strategies and immune homeostasis regulations targeting MAVS, especially focusing on the post-translational modifications of MAVS, such as ubiquitination and phosphorylation. This review summarizes the regulations of MAVS in antiviral innate immune signaling transduction and immune homeostasis maintenance.

scholarly journals Intron-containing RNA from the HIV-1 provirus activates type I interferon and inflammatory cytokines

2017 ◽  
Author(s):  
Sean Matthew McCauley ◽  
Kyusik Kim ◽  
Anetta Nowosielska ◽  
Ann Dauphin ◽  
Leonid Yurkovetskiy ◽  
...  
Keyword(s):  
T Cells ◽  
Antiviral Therapy ◽  
Antiviral Drug ◽  
Cell Types ◽  
Innate Immune ◽  
Type I ◽  
Infected People ◽  
Innate Immune Signaling ◽  
Post Transcriptional Regulation ◽  
Hiv 1

ABSTRACTHIV-1-infected people who take drugs that suppress viremia to undetectable levels are protected from developing AIDS. Nonetheless, these individuals have chronic inflammation associated with heightened risk of cardiovascular pathology. HIV-1 establishes proviruses in long-lived CD4+memory T cells, and perhaps other cell types, that preclude elimination of the virus even after years of continuous antiviral therapy. Though the majority of proviruses that persist during antiviral therapy are defective for production of infectious virions, many are expressed, raising the possibility that the HIV-1provirus or its transcripts contribute to ongoing inflammation. Here we found that the HIV-1 provirus activated innate immune signaling in isolated dendritic cells, macrophages, and CD4+T cells. Immune activation required transcription from the HIV-1 provirus and expression of CRM1-dependent, Rev-dependent, RRE-containing, unspliced HIV-1 RNA. Ifrevwas providedin trans, all HIV-1 coding sequences were dispensable for activation except thosecis-acting sequences required for replication or splicing. These results indicate that the complex, post-transcriptional regulation intrinsic to HIV-1 RNA is detected by the innate immune system as a danger signal, and that drugs which disrupt HIV-1 transcription or HIV-1 RNA metabolism would add qualitative benefit to current antiviral drug regimens.

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