cGAS-STING-mediated IFN-I response in host defense and neuro-inflammatory diseases

2021 ◽  
Vol 19 ◽  
Author(s):  
Kai Chen ◽  
Chuan Lai ◽  
Yin Su ◽  
Wen Dai Bao ◽  
Liu Nan Yang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Host Defense ◽  
Inflammatory Diseases ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Danger Signal ◽  
Downstream Signaling ◽  
Pathway Activation ◽  
Sting Pathway ◽  
Lateral Sclerosis

: The presence of foreign or misplaced nucleic acids is a danger signal that triggers innate immune responses through activating cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) and binding to its downstream signaling effector stimulator of interferon genes (STING). Then the cGAS–STING pathway activation links nucleic acid sensing to immune responses and pathogenic entities clearance. However, overactivation of this signaling pathway leads to fatal immune disorders and contributes to the progression of many human inflammatory diseases. Therefore, optimal activation of this pathway is crucial for the elimination of invading pathogens and the maintenance of immune homeostasis. In this review, we will summarize its fundamental roles in initiating host defense against invading pathogens and discuss its pathogenic roles in multiple neuro-inflammatory diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and other neurodegenerative diseases.

scholarly journals Evidence for Differential Roles for NKG2D Receptor Signaling in Innate Host Defense against Coronavirus-Induced Neurological and Liver Disease

2007 ◽  
Vol 82 (6) ◽  
pp. 3021-3030 ◽  
Author(s):  
Kevin B. Walsh ◽  
Melissa B. Lodoen ◽  
Robert A. Edwards ◽  
Lewis L. Lanier ◽  
Thomas E. Lane
Keyword(s):  
Liver Disease ◽  
Immune Responses ◽  
Host Defense ◽  
Nk Cell ◽  
Hepatitis Virus ◽  
Innate Immune ◽  
Liver Pathology ◽  
Innate Immune Responses ◽  
Ifn Γ ◽  
The Brain

ABSTRACT Infection of SCID mice with a recombinant murine coronavirus (mouse hepatitis virus [MHV]) expressing the T-cell chemoattractant CXC chemokine ligand 10 (CXCL10) resulted in increased survival and reduced viral burden within the brain and liver compared to those of mice infected with an isogenic control virus (MHV), supporting an important role for CXCL10 in innate immune responses following viral infection. Enhanced protection in MHV-CXCL10-infected mice correlated with increased gamma interferon (IFN-γ) production by infiltrating natural killer (NK) cells within the brain and reduced liver pathology. To explore the underlying mechanisms associated with protection from disease in MHV-CXCL10-infected mice, the functional contributions of the NK cell-activating receptor NKG2D in host defense were examined. The administration of an NKG2D-blocking antibody to MHV-CXCL10-infected mice did not reduce survival, dampen IFN-γ production in the brain, or affect liver pathology. However, NKG2D neutralization increased viral titers within the liver, suggesting a protective role for NKG2D signaling in this organ. These data indicate that (i) CXCL10 enhances innate immune responses, resulting in protection from MHV-induced neurological and liver disease; (ii) elevated NK cell IFN-γ expression in the brain of MHV-CXCL10-infected mice occurs independently of NKG2D; and (iii) NKG2D signaling promotes antiviral activity within the livers of MHV-infected mice that is not dependent on IFN-γ and tumor necrosis factor alpha secretion.

scholarly journals Immunologic Consequences of Hypoxia during Critical Illness

2016 ◽  
Vol 125 (1) ◽  
pp. 237-249 ◽  
Author(s):  
Harmke D. Kiers ◽  
Gert-Jan Scheffer ◽  
Johannes G. van der Hoeven ◽  
Holger K. Eltzschig ◽  
Peter Pickkers ◽  
...  
Keyword(s):  
Immune Responses ◽  
Signaling Pathways ◽  
Daily Practice ◽  
Innate Immune ◽  
Protective Effects ◽  
Innate Immune Responses ◽  
Downstream Signaling ◽  
Pathogen Clearance ◽  
Pharmacologic Modulation ◽  
Oxygen Status

Abstract Hypoxia and immunity are highly intertwined at clinical, cellular, and molecular levels. The prevention of tissue hypoxia and modulation of systemic inflammation are cornerstones of daily practice in the intensive care unit. Potentially, immunologic effects of hypoxia may contribute to outcome and represent possible therapeutic targets. Hypoxia and activation of downstream signaling pathways result in enhanced innate immune responses, aimed to augment pathogen clearance. On the other hand, hypoxia also exerts antiinflammatory and tissue-protective effects in lymphocytes and other tissues. Although human data on the net immunologic effects of hypoxia and pharmacologic modulation of downstream pathways are limited, preclinical data support the concept of tailoring the immune response through modulation of the oxygen status or pharmacologic modulation of hypoxia-signaling pathways in critically ill patients.

Deciphering the mechanism for induction of senescence-associated secretory phenotype (SASP) and its role in ageing and cancer development

2019 ◽  
Vol 166 (4) ◽  
pp. 289-295 ◽  
Author(s):  
Naoko Ohtani
Keyword(s):  
Immune Responses ◽  
Cancer Progression ◽  
Cellular Senescence ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Cycle Arrest ◽  
Secreted Factors ◽  
Suppression Mechanism ◽  
Secretory Phenotype ◽  
Sting Pathway

Abstract Cellular senescence is an irreversible form of cell cycle arrest that can be induced by persistent DNA damage, and is well known to function as an important tumour suppression mechanism. Cellular senescence is detected in aged organisms; thus, it is also recognized as a hallmark of organismal ageing. Unlike apoptotic cells, senescent cells can survive for long periods of time. Recently, it has been shown that the late stage of senescent cells are capable of expressing a variety of secreted proteins such as cytokines, chemokines and proteases, and this condition is now known as senescence-associated secretory phenotype (SASP). These secreted factors are involved in myriad of physiological functions including tissue repair and clearance of damaged cells. Alternatively, these factors may promote detrimental effects, such as chronic inflammation or cancer progression, should the SASP persist. Recent scientific advances have indicated that innate immune responses, particularly involving the cGAS–STING pathway, trigger SASP induction. Therefore, developing a strategy to regulate SASP may provide scientific insights for the management of age-associated diseases and the implementation of healthy ageing in the future.

scholarly journals “Corneal Nerves, CD11c+ Dendritic Cells and Their Impact on Ocular Immune Privilege”

2021 ◽  
Vol 12 ◽  
Author(s):  
Jerry Y. Niederkorn
Keyword(s):  
Immune Responses ◽  
Inflammatory Diseases ◽  
Innate Immune ◽  
Immune Privilege ◽  
Innate Immune Responses ◽  
Regulatory Processes ◽  
Immune Mediated ◽  
Corneal Nerves ◽  
The Central Nervous System ◽  
The Brain

The eye and the brain have limited capacities for regeneration and as such, immune-mediated inflammation can produce devastating consequences in the form of neurodegenerative diseases of the central nervous system or blindness as a result of ocular inflammatory diseases such as uveitis. Accordingly, both the eye and the brain are designed to limit immune responses and inflammation – a condition known as “immune privilege”. Immune privilege is sustained by physiological, anatomical, and regulatory processes that conspire to restrict both adaptive and innate immune responses.

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 NOD1-Mediated Mucosal Host Defense againstHelicobacter pylori

2010 ◽  
Vol 2010 ◽  
pp. 1-6 ◽  
Author(s):  
Tomohiro Watanabe ◽  
Naoki Asano ◽  
Atsushi Kitani ◽  
Ivan J. Fuss ◽  
Tsutomu Chiba ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Immune Responses ◽  
Host Defense ◽  
Molecular Mechanisms ◽  
Innate Immune ◽  
Gastric Epithelial Cells ◽  
Innate Immune Responses ◽  
Cytokines And Chemokines ◽  
H Pylori ◽  
Oligomerization Domain

Infection of the stomach withHelicobacter pyloriis an important risk factor for gastritis, peptic ulcer, and gastric carcinoma. Although it has been well established that persistent colonization byH. pyloriis associated with adaptive Th1 responses, the innate immune responses leading to these Th1 responses are poorly defined. Recent studies have shown that the activation of nucleotide-binding oligomerization domain 1 (NOD1) in gastric epithelial cells plays an important role in innate immune responses againstH. pylori. The detection ofH. pylori-derived ligands by cytosolic NOD1 induces several host defense factors, including antimicrobial peptides, cytokines, and chemokines. In this paper, we review the molecular mechanisms by which NOD1 contributes to mucosal host defense againstH. pyloriinfection of the stomach.

scholarly journals IL-17A in Human Respiratory Diseases: Innate or Adaptive Immunity? Clinical Implications

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Dominique M. A. Bullens ◽  
Ann Decraene ◽  
Sven Seys ◽  
Lieven J. Dupont
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Respiratory Diseases ◽  
Inflammatory Diseases ◽  
Cell Lineage ◽  
Innate Immune ◽  
Clinical Implications ◽  
Innate Immune Cells ◽  
Innate Immune Responses

Since the discovery of IL-17 in 1995 as a T-cell cytokine, inducing IL-6 and IL-8 production by fibroblasts, and the report of a separate T-cell lineage producing IL-17(A), called Th17 cells, in 2005, the role of IL-17 has been studied in several inflammatory diseases. By inducing IL-8 production and subsequent neutrophil attraction towards the site of inflammation, IL-17A can link adaptive and innate immune responses. More specifically, its role in respiratory diseases has intensively been investigated. We here review its role in human respiratory diseases and try to unravel the question whether IL-17A only provides a link between the adaptive and innate respiratory immunity or whether this cytokine might also be locally produced by innate immune cells. We furthermore briefly discuss the possibility to reduce local IL-17A production as a treatment option for respiratory diseases.

Dual-specificity phosphatase 1: a critical regulator of innate immune responses

2006 ◽  
Vol 34 (6) ◽  
pp. 1018-1023 ◽  
Author(s):  
S.M. Abraham ◽  
A.R. Clark
Keyword(s):  
Innate Immunity ◽  
Immune Responses ◽  
P38 Mapk ◽  
Time Course ◽  
Inflammatory Diseases ◽  
Innate Immune ◽  
Mitogen Activated Protein Kinase ◽  
Innate Immune Responses ◽  
Inflammatory Stimuli ◽  
Mitogen Activated Protein

Innate immune responses are critically dependent on MAPK (mitogen-activated protein kinase) signalling pathways, in particular JNK (c-Jun N-terminal kinase) and p38 MAPK. Both of these kinases are negatively regulated via their dephosphorylation by DUSP1 (dual­-specificity phosphatase 1). Several pro- and anti-inflammatory stimuli converge to regulate the DUSP1 gene and to modulate the time course of its expression. In turn, the pattern of expression of DUSP1 dictates the kinetics of activation of JNK and p38 MAPK, and this influences the expression of several mediators of innate immunity. DUSP1 is therefore a central regulator of innate immunity, and its expression can profoundly affect the outcome of inflammatory challenges. We discuss possible implications for immune-mediated inflammatory diseases and their treatment.

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