scholarly journals Intrinsic antiproliferative activity of the innate sensor STING in T lymphocytes

2017 ◽  
Vol 214 (6) ◽  
pp. 1769-1785 ◽  
Author(s):  
Silvia Cerboni ◽  
Nadia Jeremiah ◽  
Matteo Gentili ◽  
Ulf Gehrmann ◽  
Cécile Conrad ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Immune Responses ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Type I ◽  
Innate Immune Responses ◽  
Inflammatory Gene Expression ◽  
Adaptive Immune ◽  
Cyclic Dinucleotide

Activation of the cyclic dinucleotide sensor stimulator of interferon (IFN) genes (STING) is critical for IFN and inflammatory gene expression during innate immune responses. However, the role of STING in adaptive immunity is still unknown. In this study, we show that STING activation reduces the proliferation of T lymphocytes. This activity was independent of TBK1 and IRF3 recruitment and of type I IFN but required a distinct C-terminal domain of STING that activates NF-κB. Inhibition of cell proliferation by STING required its relocalization to the Golgi apparatus and caused mitotic errors. T lymphocytes from patients carrying constitutive active mutations in TMEM173 encoding STING showed impaired proliferation and reduced numbers of memory cells. Endogenous STING inhibited proliferation of mouse T lymphocytes. Therefore, STING, a critical innate sensor, also functions intrinsically in cells of the adaptive immune system to inhibit proliferation.

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 The neuropeptide receptor NMUR-1 regulates the specificity of C. elegans innate immunity against pathogen infection

2021 ◽  
Author(s):  
Phillip Wibisono ◽  
Shawndra Wibisono ◽  
Jan Watteyne ◽  
Chia-Hui Chen ◽  
Durai Sellegounder ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Immune Responses ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Immune Genes ◽  
C Elegans ◽  
Adaptive Immune ◽  
Functional Assays

A key question in current immunology is how the innate immune system generates high levels of specificity. Like most invertebrates, Caenorhabditis elegans does not have an adaptive immune system and relies solely on innate immunity to defend itself against pathogen attacks, yet it can still differentiate different pathogens and launch distinct innate immune responses. Here, we have found that functional loss of NMUR-1, a neuronal GPCR homologous to mammalian receptors for the neuropeptide neuromedin U, has diverse effects on C. elegans survival against various bacterial pathogens. Transcriptomic analyses and functional assays revealed that NMUR-1 modulates C. elegans transcription activity by regulating the expression of transcription factors, which, in turn, controls the expression of distinct immune genes in response to different pathogens. Our study has uncovered a molecular basis for the specificity of C. elegans innate immunity that could provide mechanistic insights into understanding the specificity of vertebrate innate immunity.

scholarly journals Integrated role of microRNA-30e-5p through targeting negative regulators of innate immune pathways during HBV infection and SLE

2020 ◽  
Author(s):  
Richa Mishra ◽  
Sanjana Bhattacharya ◽  
Bhupendra S Rawat ◽  
Ashish Kumar ◽  
Akhilesh Kumar ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Mouse Model ◽  
Immune Responses ◽  
Therapeutic Potential ◽  
Innate Immune ◽  
Locked Nucleic Acid ◽  
Type I ◽  
Innate Immune Responses ◽  
Negative Regulators

AbstractPrecise regulation of innate immunity is crucial for the development of appropriate host immunity against microbial infections and the maintenance of immune homeostasis. The microRNAs are small non-coding RNA, post-transcriptional regulator of multiple genes and act as a rheostat for protein expression. Here, we identified microRNA(miR)-30e-5p (miR-30e) induced by the hepatitis B virus (HBV) and other viruses that act as a master regulator for innate immune responses. Moreover, pegylated type I interferons treatment to HBV patients for viral reduction also reduces the miRNA. Additionally, we have also shown the immuno-pathological effects of miR-30e in systemic lupus erythematous (SLE) patients and SLE mouse model. Mechanistically, the miR-30e targets multiple negative regulators namely TRIM38, TANK, ATG5, ATG12, BECN1, SOCS1, SOCS3 of innate immune signaling pathways and enhances innate immune responses. Furthermore, sequestering of endogenous miR-30e in PBMCs of SLE patients and SLE mouse model respectively by the introduction of antagomir and locked nucleic acid based inhibitor significantly reduces type I interferon and pro-inflammatory cytokines. Collectively, our study demonstrates the novel role of miR-30e in innate immunity and its prognostic and therapeutic potential in infectious and autoimmune diseases.

SLPI and elafin: one glove, many fingers

2005 ◽  
Vol 110 (1) ◽  
pp. 21-35 ◽  
Author(s):  
Steven E. Williams ◽  
Thomas I. Brown ◽  
Ali Roghanian ◽  
Jean-Michel Sallenave
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Immune Responses ◽  
Adaptive Immune Response ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Type I ◽  
Adaptive Immune ◽  
Pathological Conditions ◽  
Related Proteins

Elafin and SLPI (secretory leucocyte protease inhibitor) have multiple important roles both in normal homoeostasis and at sites of inflammation. These include antiprotease and antimicrobial activity as well as modulation of the response to LPS (lipopolysaccharide) stimulation. Elafin and SLPI are members of larger families of proteins secreted predominantly at mucosal sites, and have been shown to be modulated in multiple pathological conditions. We believe that elafin and SLPI are important molecules in the controlled functioning of the innate immune system, and may have further importance in the integration of this system with the adaptive immune response. Recent interest has focused on the influence of inflamed tissues on the recruitment and phenotypic modulation of cells of the adaptive immune system and, indeed, the local production of elafin and SLPI indicate that they are ideally placed in this regard. Functionally related proteins, such as the defensins and cathelicidins, have been shown to have direct effects upon dendritic cells with potential alteration of their phenotype towards type I or II immune responses. This review addresses the multiple functions of elafin and SLPI in the inflammatory response and discusses further their roles in the development of the adaptive immune response.

scholarly journals Polymorphisms in STING affect human innate immune responses to poxviruses

2020 ◽  
Author(s):  
Richard B. Kennedy ◽  
Iana H. Haralambieva ◽  
Inna G. Ovsyannikova ◽  
Emily A. Voigt ◽  
Beth R. Larrabee ◽  
...  
Keyword(s):  
Immune Response ◽  
Molecular Modeling ◽  
Immune Responses ◽  
Genetic Variants ◽  
Innate Immune ◽  
Smallpox Vaccination ◽  
Type I ◽  
Innate Immune Responses ◽  
Dna Viruses

AbstractWe conducted a large genome-wide association study (GWAS) of the immune responses to primary smallpox vaccination in a combined cohort of > 1,600 subjects. We identified a cluster of SNPs on chromosome 5 (5q31.2) that were significantly associated (p-value: 1.3 × 10−12 – 1.5×10−36) with IFNα response to in vitro poxvirus stimulation. Examination of these SNPs led to the functional testing of rs1131769, a non-synonymous SNP in TMEM173 causing an Arg-to-His change at position 232 in the STING protein—a major regulator of innate immune responses to viral infections. Our findings demonstrate important functional differences between the two alleles, where the major allele (R232) more effectively induces IFNα secretion. Molecular modeling of both alleles identified altered ligand binding characteristics between the two variants, providing a potential mechanism underlying differences in inter-individual responses to poxvirus vaccination. Our data demonstrate that possession of the H232 variant impairs STING-mediated innate immunity to poxviruses. These results clarify prior studies evaluating functional effects of genetic variants in TMEM173 and provide novel data regarding genetic control of poxvirus immunity.Contribution to the FieldHere we report that a single nucleotide non-synonymous polymorphism in the TMEM173 gene encodes for a STING variant conferring a reduced IFN stimulated response compared to wild type. Our results suggest that, upon binding of the STING H232 variant to its ligand, activation of downstream signaling proteins is impaired, resulting in decreased production of IFNα and a weaker interferon-stimulated gene response. Molecular modeling indicates that the diminished functional activity of this variant is likely due to an altered physical structure of the STING protein. STING controls the innate, type I IFN response to double-stranded DNA and cyclic dinucleotides. Individuals with the H232 variant of STING have a much weaker innate immune response to vaccinia virus. Our data help resolve ongoing controversies regarding the role of genetic variants in STING function. Because STING plays an important role in our immune response to DNA viruses and bacteria, our results can be used to predict who will and will not respond to vaccines and treatments, and to design more effective vaccine candidates. Given the role of the STING protein in innate responses to DNA viruses and bacterial pathogens, these data may also be useful in developing novel treatment options for multiple infectious diseases.

Coordinate actions of innate immune responses oppose those of the adaptive immune system duringSalmonellainfection of mice

2016 ◽  
Vol 9 (410) ◽  
pp. ra4-ra4 ◽  
Author(s):  
Andrew N. Hotson ◽  
Smita Gopinath ◽  
Monica Nicolau ◽  
Anna Khasanova ◽  
Rachel Finck ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Adaptive Immune

The Emerging Role of B Lymphocytes in Cardiovascular Disease

2020 ◽  
Vol 38 (1) ◽  
pp. 99-121
Author(s):  
Luigi Adamo ◽  
Cibele Rocha-Resende ◽  
Douglas L. Mann
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
B Lymphocytes ◽  
Cell Biology ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Review Of The Literature ◽  
Adaptive Immune

B cells are traditionally known for their ability to produce antibodies in the context of adaptive immune responses. However, over the last decade B cells have been increasingly recognized as modulators of both adaptive and innate immune responses, as well as players in an important role in the pathogenesis of a variety of human diseases. Here, after briefly summarizing our current understanding of B cell biology, we present a systematic review of the literature from both animal models and human studies that highlight the important role that B lymphocytes play in cardiac and vascular disease. While many aspects of B cell biology in the vasculature and, to an even greater extent, in the heart remain unclear, B cells are emerging as key regulators of cardiovascular adaptation to injury.

scholarly journals The Function of cGAS-STING Pathway in Treatment of Pancreatic Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Ghazal Mohseni ◽  
Juan Li ◽  
Abakundana Nsenga Ariston Gabriel ◽  
Lutao Du ◽  
Yun-shan Wang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Immune Responses ◽  
Adaptive Immune System ◽  
Type I Interferons ◽  
Pancreatic Tumors ◽  
Type I ◽  
Adaptive Immune ◽  
Combination Methods ◽  
Sting Pathway

The activation of stimulator of interferon genes (STING) signalling pathway has been suggested to promote the immune responses against malignancy. STING is activated in response to the detection of cytosolic DNA and can induce type I interferons and link innate immunity with the adaptive immune system. Due to accretive evidence demonstrating that the STING pathway regulates the immune cells of the tumor microenvironment (TME), STING as a cancer biotherapy has attracted considerable attention. Pancreatic cancer, with a highly immunosuppressive TME, remains fatal cancer. STING has been applied to the treatment of pancreatic cancer through distinct strategies. This review reveals the role of STING signalling on pancreatic tumors and other diseases related to the pancreas. We then discuss new advances of STING in either monotherapy or combination methods for pancreatic cancer immunotherapy.

scholarly journals The PD-L1/PD-1 Axis Blocks Neutrophil Cytotoxicity in Cancer

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1510
Author(s):  
Olga Yajuk ◽  
Maya Baron ◽  
Sapir Toker ◽  
Tamir Zelter ◽  
Tanya Fainsod-Levi ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Therapeutic Potential ◽  
Cytotoxic T Cells ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Adaptive Immune

The PD-L1/PD-1 axis mediates immune tolerance and promotes tumor growth and progression via the inhibition of anti-tumor immunity. Blocking the interaction between PD-L1 and PD-1 was clinically shown to be beneficial in maintaining the anti-tumor functions of the adaptive immune system. Still, the consequences of blocking the PD-L1/PD-1 axis on innate immune responses remain largely unexplored. In this context, neutrophils were shown to consist of distinct subpopulations, which possess either pro- or anti-tumor properties. PD-L1-expressing neutrophils are considered pro-tumor as they are able to suppress cytotoxic T cells and are propagated with disease progression. That said, we found that PD-L1 expression is not limited to tumor promoting neutrophils, but is also evident in anti-tumor neutrophils. We show that neutrophil cytotoxicity is effectively and efficiently blocked by tumor cell-expressed PD-1. Furthermore, the blocking of either neutrophil PD-L1 or tumor cell PD-1 maintains neutrophil cytotoxicity. Importantly, we show that tumor cell PD-1 blocks neutrophil cytotoxicity and promotes tumor growth via a mechanism independent of adaptive immunity. Taken together, these findings highlight the therapeutic potential of enhancing anti-tumor innate immune responses via blocking of the PD-L1/PD-1 axis.

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