scholarly journals Type I Interferons as Joint Regulators of Tumor Growth and Obesity

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 196
Author(s):  
Sandra Gessani ◽  
Filippo Belardelli
Keyword(s):  
Tumor Growth ◽  
Mouse Models ◽  
Inflammatory Responses ◽  
Tumor Development ◽  
Cancer Control ◽  
Type I Interferons ◽  
Type I ◽  
Diet Induced Obesity ◽  
Background Diet ◽  
Tumor Persistence

Type I interferons (IFN-I) are antiviral cytokines endowed with multiple biological actions, including antitumor activity. Studies in mouse models and cancer patients support the concept that endogenous IFN-I play important roles in the control of tumor development and growth as well as in response to several chemotherapy/radiotherapy treatments. While IFN-I signatures in the tumor microenvironment are often considered as biomarkers for a good prognostic response to antitumor therapies, prolonged IFN-I signaling can lead to immune dysfunction, thereby promoting pathogen or tumor persistence, thus revealing the “Janus face” of these cytokines in cancer control, likely depending on timing, tissue microenvironment and cumulative levels of IFN-I signals. Likewise, IFN-I exhibit different and even opposite effects on obesity, a pathologic condition linked to cancer development and growth. As an example, evidence obtained in mouse models shows that localized expression of IFN-I in the adipose tissue results in inhibition of diet–induced obesity, while hyper-production of these cytokines by specialized cells such as plasmacytoid dendritic cells in the same tissue, can induce systemic inflammatory responses leading to obesity. Further studies in mouse models and humans should reveal the mechanisms by which IFN-I can regulate both tumor growth and obesity and to understand the role of factors such as genetic background, diet and microbioma in shaping the production and action of these cytokines under physiological and pathological conditions.

scholarly journals Increased Tumor Growth in Mice with Diet-Induced Obesity: Impact of Ovarian Hormones

Endocrinology ◽  
2006 ◽  
Vol 147 (12) ◽  
pp. 5826-5834 ◽  
Author(s):  
Shoshana Yakar ◽  
Nomeli P. Nunez ◽  
Patricia Pennisi ◽  
Pnina Brodt ◽  
Hui Sun ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Tumor Growth ◽  
Glucose Intolerance ◽  
Tumor Development ◽  
Tumor Growth Rate ◽  
Obese Mice ◽  
Female Mice ◽  
Diet Induced Obesity ◽  
Body Adiposity ◽  
Obese Female

Obesity increases the risk of many cancers in both males and females. This study describes a link between obesity, obesity-associated metabolic alterations, and the risk of developing cancer in male and female mice. The goal of this study was to evaluate the relationship between gender and obesity and to determine the role of estrogen status in obese females and its effect on tumor growth. We examined the susceptibility of C57BL/6 mice to diet-induced obesity, insulin resistance/glucose intolerance, and tumors. Mice were injected sc with one of two tumorigenic cell lines, Lewis lung carcinoma, or mouse colon 38-adenocarcinoma. Results show that tumor growth rate was increased in obese mice vs. control mice irrespective of the tumor cell type. To investigate the effect of estrogen status on tumor development in obese females, we compared metabolic parameters and tumor growth in ovariectomized (ovx) and intact obese female mice. Obese ovx female mice developed insulin resistance and glucose intolerance similar to that observed in obese males. Our results demonstrate that body adiposity increased in ovx females irrespective of the diet administered and that tumor growth correlated positively with body adiposity. Overall, these data point to more rapid tumor growth in obese mice and suggest that endogenous sex steroids, together with diet, affect adiposity, insulin sensitivity, and tumor growth in female mice.

scholarly journals Danger-Associated Molecular Patterns (DAMPs): Molecular Triggers for Sterile Inflammation in the Liver

2018 ◽  
Vol 19 (10) ◽  
pp. 3104 ◽  
Author(s):  
Sabine Mihm
Keyword(s):  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Sterile Inflammation ◽  
Type I Interferons ◽  
Neutrophil Granulocytes ◽  
Type I ◽  
Hepatic Ischemia ◽  
Hepatic Ischemia Reperfusion ◽  
Molecular Patterns

Inflammatory liver diseases in the absence of pathogens such as intoxication by xenobiotics, cholestatic liver injury, hepatic ischemia-reperfusion injury (I/R), non-alcoholic steatohepatitis (NASH), or alcoholic liver disease (ALD) remain threatening conditions demanding specific therapeutic options. Caused by various different noxae, all these conditions have been recognized to be triggered by danger- or death-associated molecular patterns (DAMPs), discompartmentalized self-structures released by dying cells. These endogenous, ectopic molecules comprise proteins, nucleic acids, adenosine triphosphate (ATP), or mitochondrial compounds, among others. This review resumes the respective modes of their release—passively by necrotic hepatocytes or actively by viable or apoptotic parenchymal cells—and their particular roles in sterile liver pathology. It addresses their sensors and the initial inflammatory responses they provoke. It further addresses a resulting second wave of parenchymal death that might be of different mode, boosting the release of additional, second-line DAMPs. Thus, triggering a more complex and pronounced response. Initial and secondary inflammatory responses comprise the activation of Kupffer cells (KCs), the attraction and activation of monocytes and neutrophil granulocytes, and the induction of type I interferons (IFNs) and their effectors. A thorough understanding of pathophysiology is a prerequisite for identifying rational therapeutic targets.

scholarly journals Autophagy Inhibits Grass Carp Reovirus (GCRV) Replication and Protects Ctenopharyngodon idella Kidney (CIK) Cells from Excessive Inflammatory Responses after GCRV Infection

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1296
Author(s):  
Pengfei Chu ◽  
Libo He ◽  
Rong Huang ◽  
Lanjie Liao ◽  
Yongming Li ◽  
...  
Keyword(s):  
Virus Replication ◽  
Grass Carp ◽  
Inflammatory Responses ◽  
Early Stage ◽  
Tracer Tests ◽  
Type I Interferons ◽  
Ctenopharyngodon Idella ◽  
Type I ◽  
Grass Carp Reovirus ◽  
Cik Cells

Autophagy is an essential and highly conserved process in mammals, which is critical to maintaining physiological homeostasis, including cell growth, development, repair, and survival. However, the understanding of autophagy in fish virus replication is limited. In this study, we found that grass carp reovirus (GCRV) infection stimulated autophagy in the spleen of grass carp (Ctenopharyngodon idella). Moreover, both Western blot (WB) analysis and fluorescent tracer tests showed that GCRV infection induced the enhancement of autophagy activation in Ctenopharyngodon idella kidney (CIK) cells. Autophagy inducer rapamycin and autophagy inhibitor 3-MA pretreatment can inhibit and promote the proliferation of GCRV, respectively. In addition, grass carp autophagy-related gene 5 (CiATG5)-induced autophagy, as well as rapamycin, showed effects on GCRV replication in CIK cells. Transcriptome analysis revealed that the total number of differentially expressed genes (DEGs) in CiATG5 overexpression groups was less than that of the control during GCRV infection. Enrichment analysis showed that CiATG5 overexpression induced the enhancement of autophagy, lysosome, phagosome, and apoptosis in the early stage of GCRV infection, which led to the clearance of viruses. In the late stage, steroid biosynthesis, DNA replication, terpenoid backbone biosynthesis, and carbon metabolism were upregulated, which contributed to cell survival. Moreover, signaling pathways involved in the immune response and cell death were downregulated in CiATG5 overexpression groups. Further study showed that CiATG5 repressed the expression of inflammatory response genes, including cytokines and type I interferons. Taken together, the results demonstrate that autophagy represses virus replication and attenuates acute inflammatory responses to protect cells.

scholarly journals How the Innate Immune DNA Sensing cGAS–STING Pathway Is Involved in Autophagy

2021 ◽  
Vol 22 (24) ◽  
pp. 13232
Author(s):  
Wanglong Zheng ◽  
Nengwen Xia ◽  
Jiajia Zhang ◽  
Nanhua Chen ◽  
François Meurens ◽  
...  
Keyword(s):  
Immune Responses ◽  
Inflammatory Responses ◽  
Complex Interaction ◽  
Innate Immune ◽  
Type I Interferons ◽  
Type I ◽  
Innate Immune Responses ◽  
Homeostatic Process ◽  
Sting Pathway ◽  
Dna Complex

The cGAS–STING pathway is a key component of the innate immune system and exerts crucial roles in the detection of cytosolic DNA and invading pathogens. Accumulating evidence suggests that the intrinsic cGAS–STING pathway not only facilitates the production of type I interferons (IFN-I) and inflammatory responses but also triggers autophagy. Autophagy is a homeostatic process that exerts multiple effects on innate immunity. However, systematic evidence linking the cGAS–STING pathway and autophagy is still lacking. Therefore, one goal of this review is to summarize the known mechanisms of autophagy induced by the cGAS–STING pathway and their consequences. The cGAS–STING pathway can trigger canonical autophagy through liquid-phase separation of the cGAS–DNA complex, interaction of cGAS and Beclin-1, and STING-triggered ER stress–mTOR signaling. Furthermore, both cGAS and STING can induce non-canonical autophagy via LC3-interacting regions and binding with LC3. Subsequently, autophagy induced by the cGAS–STING pathway plays crucial roles in balancing innate immune responses, maintaining intracellular environmental homeostasis, alleviating liver injury, and limiting tumor growth and transformation.

scholarly journals Impact of STING Inflammatory Signaling during Intracellular Bacterial Infections

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 74
Author(s):  
Erika S. Guimarães ◽  
Fabio V. Marinho ◽  
Nina M. G. P. de Queiroz ◽  
Maísa M. Antunes ◽  
Sergio C. Oliveira
Keyword(s):  
Immune Responses ◽  
Bacterial Infections ◽  
Inflammatory Responses ◽  
Metabolic Reprogramming ◽  
Host Cells ◽  
Type I Interferons ◽  
Type I ◽  
Bacterial Survival ◽  
Inflammatory Profile ◽  
The Impact

The early detection of bacterial pathogens through immune sensors is an essential step in innate immunity. STING (Stimulator of Interferon Genes) has emerged as a key mediator of inflammation in the setting of infection by connecting pathogen cytosolic recognition with immune responses. STING detects bacteria by directly recognizing cyclic dinucleotides or indirectly by bacterial genomic DNA sensing through the cyclic GMP-AMP synthase (cGAS). Upon activation, STING triggers a plethora of powerful signaling pathways, including the production of type I interferons and proinflammatory cytokines. STING activation has also been associated with the induction of endoplasmic reticulum (ER) stress and the associated inflammatory responses. Recent reports indicate that STING-dependent pathways participate in the metabolic reprogramming of macrophages and contribute to the establishment and maintenance of a robust inflammatory profile. The induction of this inflammatory state is typically antimicrobial and related to pathogen clearance. However, depending on the infection, STING-mediated immune responses can be detrimental to the host, facilitating bacterial survival, indicating an intricate balance between immune signaling and inflammation during bacterial infections. In this paper, we review recent insights regarding the role of STING in inducing an inflammatory profile upon intracellular bacterial entry in host cells and discuss the impact of STING signaling on the outcome of infection. Unraveling the STING-mediated inflammatory responses can enable a better understanding of the pathogenesis of certain bacterial diseases and reveal the potential of new antimicrobial therapy.

scholarly journals An activated form of ADAM10 is tumor selective and regulates cancer stem-like cells and tumor growth

2016 ◽  
Vol 213 (9) ◽  
pp. 1741-1757 ◽  
Author(s):  
Lakmali Atapattu ◽  
Nayanendu Saha ◽  
Chanly Chheang ◽  
Moritz F. Eissman ◽  
Kai Xu ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Mouse Models ◽  
Active Form ◽  
Tumor Development ◽  
Surface Proteins ◽  
Active Conformation ◽  
Normal Tissues ◽  
Promising Therapeutic Target ◽  
Targeted Inhibition ◽  
Disulfide Isomerization

The transmembrane metalloprotease ADAM10 sheds a range of cell surface proteins, including ligands and receptors of the Notch, Eph, and erbB families, thereby activating signaling pathways critical for tumor initiation and maintenance. ADAM10 is thus a promising therapeutic target. Although widely expressed, its activity is normally tightly regulated. We now report prevalence of an active form of ADAM10 in tumors compared with normal tissues, in mouse models and humans, identified by our conformation-specific antibody mAb 8C7. Structure/function experiments indicate mAb 8C7 binds an active conformation dependent on disulfide isomerization and oxidative conditions, common in tumors. Moreover, this active ADAM10 form marks cancer stem-like cells with active Notch signaling, known to mediate chemoresistance. Importantly, specific targeting of active ADAM10 with 8C7 inhibits Notch activity and tumor growth in mouse models, particularly regrowth after chemotherapy. Our results indicate targeted inhibition of active ADAM10 as a potential therapy for ADAM10-dependent tumor development and drug resistance.

scholarly journals HIV-1 Unspliced RNA Expression Induces Innate Immune Activation in Macrophages

2017 ◽  
Author(s):  
Hisashi Akiyama ◽  
Caitlin M. Miller ◽  
Chelsea R. Ettinger ◽  
Anna C. Belkina ◽  
Jennifer Snyder-Cappione ◽  
...  
Keyword(s):  
Immune Activation ◽  
Highly Active Antiretroviral Therapy ◽  
Nuclear Export ◽  
Inflammatory Responses ◽  
Type I Interferons ◽  
Rna Expression ◽  
Type I ◽  
Hiv Rna ◽  
Highly Active ◽  
Hiv 1

ABSTRACTLow-levels of type I interferons (IFN-I) are thought to be a driving force for immune activation and T cell exhaustion in HIV-1 infected individuals on highly active antiretroviral therapy (HAART), though the causative mechanisms for persistent IFN-I signaling have remained unclear. Here, we show Rev-CRM1 dependent nuclear export and peripheral membrane association of intron-containing HIV-1 unspliced RNA (usRNA), independent of primary viral sequence or viral protein expression, is subject to sensing, and results in IFN-I-dependent pro-inflammatory responses in macrophages. Our findings suggest that persistent expression of HIV-1 usRNA in macrophages contributes to chronic immune activation and that use of HIV RNA expression inhibitors as adjunct therapy might abrogate aberrant inflammation and restore immune function in HIV-infected individuals on HAART.

scholarly journals Traumatic Brain Injury Induces cGAS Activation and Type I Interferon Signaling in Aged Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
James P. Barrett ◽  
Susan M. Knoblach ◽  
Surajit Bhattacharya ◽  
Heather Gordish-Dressman ◽  
Bogdan A. Stoica ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Inflammatory Responses ◽  
Type I Interferons ◽  
Type I ◽  
Post Injury ◽  
Age Related ◽  
Inflammatory Processes ◽  
Sting Pathway ◽  
Induced Changes

Aging adversely affects inflammatory processes in the brain, which has important implications in the progression of neurodegenerative disease. Following traumatic brain injury (TBI), aged animals exhibit worsened neurological function and exacerbated microglial-associated neuroinflammation. Type I Interferons (IFN-I) contribute to the development of TBI neuropathology. Further, the Cyclic GMP-AMP Synthase (cGAS) and Stimulator of Interferon Genes (STING) pathway, a key inducer of IFN-I responses, has been implicated in neuroinflammatory activity in several age-related neurodegenerative diseases. Here, we set out to investigate the effects of TBI on cGAS/STING activation, IFN-I signaling and neuroinflammation in young and aged C57Bl/6 male mice. Using a controlled cortical impact model, we evaluated transcriptomic changes in the injured cortex at 24 hours post-injury, and confirmed activation of key neuroinflammatory pathways in biochemical studies. TBI induced changes were highly enriched for transcripts that were involved in inflammatory responses to stress and host defense. Deeper analysis revealed that TBI increased expression of IFN-I related genes (e.g. Ifnb1, Irf7, Ifi204, Isg15) and IFN-I signaling in the injured cortex of aged compared to young mice. There was also a significant age-related increase in the activation of the DNA-recognition pathway, cGAS, which is a key mechanism to propagate IFN-I responses. Finally, enhanced IFN-I signaling in the aged TBI brain was confirmed by increased phosphorylation of STAT1, an important IFN-I effector molecule. This age-related activation of cGAS and IFN-I signaling may prove to be a mechanistic link between microglial-associated neuroinflammation and neurodegeneration in the aged TBI brain.

scholarly journals Engineering supramolecular organizing centers for optogenetic control of innate immune responses

2020 ◽  
Author(s):  
Peng Tan ◽  
Lian He ◽  
Yubin Zhou
Keyword(s):  
Transcriptional Activation ◽  
Inflammatory Responses ◽  
Protein Complexes ◽  
Innate Immune ◽  
Type I Interferons ◽  
Type I ◽  
Dependent Manner ◽  
Innate Immune Responses ◽  
Spatiotemporal Resolution ◽  
Oligomeric Protein

AbstractThe spatiotemporal organization of oligomeric protein complexes and translocons, such as the supramolecular organizing centers (SMOC) made of MyDDosome and MAVSome, are essential for transcriptional activation of host inflammatory responses and immune metabolisms. Light-inducible assembly of MyDDosome and MAVSome are presented herein to induce activation of nuclear factor-kB (NF-κB) and type-I interferons (IFNs). Engineering of SMOCs and the downstream transcription factor permits programmable and customized innate immune operations in a light-dependent manner. These synthetic molecular tools will likely enable optical and user-defined modulation of innate immunity at a high spatiotemporal resolution to facilitate mechanistic studies of distinct modes of innate immune activations and potential intervention of immune disorders and cancer.

microRNA-20-1 and miR-101a suppress the NF-κB-mediated inflammation production by targeting TRAF6 in miiuy croaker

2021 ◽  
Author(s):  
Junxia Cui ◽  
Liping Gu ◽  
Lichang Zhong ◽  
Xuezhu Liu ◽  
Yuena Sun ◽  
...  
Keyword(s):  
Immune Response ◽  
Inflammatory Cytokines ◽  
Regulatory Networks ◽  
Inflammatory Responses ◽  
Type I Interferons ◽  
Type I ◽  
Negative Regulators ◽  
Lower Vertebrates ◽  
Inhibit Gene Expression ◽  
Insight Into

Upon recognition of the pathogen components by PRR (pattern recognition receptors), then the cells could be activated to produce inflammatory cytokines and type I interferons. The inflammation is tightly modulated by the host to prevent inappropriate inflammatory responses. MicroRNAs (miRNAs) are non-coding and small RNAs that can inhibit gene expression and participate in various biological functions, including maintaining a balanced immune response in the host. To maintain the balance of the immune response, these pathways are closely regulated by the host to prevent inappropriate reactions of the cells. However, in low vertebrates, the miRNA-mediated inflammatory response regulatory networks remain largely unknown. Here, we report that two miRNAs, miR-20-1 and miR-101a are identified as negative regulators in teleost inflammatory responses. Initially, we find that both miR-20-1 and miR-101a dramatically increased after lipopolysaccharide (LPS) stimulation and Vibrio harveyi infection. Upregulated miR-20-1 and miR-101a inhibit LPS-induced inflammatory cytokines production by targeting TNF receptor-associated factor 6 (TRAF6), thus avoiding excessive inflammation. Moreover, miR-20-1 and miR-101a regulate the inflammatory responses through the TRAF6-mediated nuclear factor kappa (NF-κB) signaling pathways. Collectively, these data indicate that miR-20-1 and miR-101a act as negative regulators through regulating the TRAF6-mediated NF-κB signaling pathway, and participate in the host antibacterial immune responses, which will provide new insight into the intricate networks of the host-pathogen interaction in the lower vertebrates.

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