scholarly journals Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential

2011 ◽  
Vol 121 (9) ◽  
pp. 367-387 ◽  
Author(s):  
Mark L. Hanke ◽  
Tammy Kielian
Keyword(s):  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Tissue Injury ◽  
Microbial Pathogens ◽  
Type I ◽  
Toll Like Receptors ◽  
Microbial Infection ◽  
Cns Disorders ◽  
The Brain ◽  
Tlr Signalling

The discovery of mammalian TLRs (Toll-like receptors), first identified in 1997 based on their homology with Drosophila Toll, greatly altered our understanding of how the innate immune system recognizes and responds to diverse microbial pathogens. TLRs are evolutionarily conserved type I transmembrane proteins expressed in both immune and non-immune cells, and are typified by N-terminal leucine-rich repeats and a highly conserved C-terminal domain termed the TIR [Toll/interleukin (IL)-1 receptor] domain. Upon stimulation with their cognate ligands, TLR signalling elicits the production of cytokines, enzymes and other inflammatory mediators that can have an impact on several aspects of CNS (central nervous system) homoeostasis and pathology. For example, TLR signalling plays a crucial role in initiating host defence responses during CNS microbial infection. Furthermore, TLRs are targets for many adjuvants which help shape pathogen-specific adaptive immune responses in addition to triggering innate immunity. Our knowledge of TLR expression and function in the CNS has greatly expanded over the last decade, with new data revealing that TLRs also have an impact on non-infectious CNS diseases/injury. In particular, TLRs recognize a number of endogenous molecules liberated from damaged tissues and, as such, influence inflammatory responses during tissue injury and autoimmunity. In addition, recent studies have implicated TLR involvement during neurogenesis, and learning and memory in the absence of any underlying infectious aetiology. Owing to their presence and immune-regulatory role within the brain, TLRs represent an attractive therapeutic target for numerous CNS disorders and infectious diseases. However, it is clear that TLRs can exert either beneficial or detrimental effects in the CNS, which probably depend on the context of tissue homoeostasis or pathology. Therefore any potential therapeutic manipulation of TLRs will require an understanding of the signals governing specific CNS disorders to achieve tailored therapy.

Detection of Microbial Infections Through Innate Immune Sensing of Nucleic Acids

2018 ◽  
Vol 72 (1) ◽  
pp. 447-478 ◽  
Author(s):  
Xiaojun Tan ◽  
Lijun Sun ◽  
Jueqi Chen ◽  
Zhijian J. Chen
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Immune Defense ◽  
Innate Immune ◽  
Type I Interferons ◽  
Microbial Pathogens ◽  
Type I ◽  
Immune Recognition ◽  
Microbial Infection ◽  
Microbial Infections

Microbial infections are recognized by the innate immune system through germline-encoded pattern recognition receptors (PRRs). As most microbial pathogens contain DNA and/or RNA during their life cycle, nucleic acid sensing has evolved as an essential strategy for host innate immune defense. Pathogen-derived nucleic acids with distinct features are recognized by specific host PRRs localized in endolysosomes and the cytosol. Activation of these PRRs triggers signaling cascades that culminate in the production of type I interferons and proinflammatory cytokines, leading to induction of an antimicrobial state, activation of adaptive immunity, and eventual clearance of the infection. Here, we review recent progress in innate immune recognition of nucleic acids upon microbial infection, including pathways involving endosomal Toll-like receptors, cytosolic RNA sensors, and cytosolic DNA sensors. We also discuss the mechanisms by which infectious microbes counteract host nucleic acid sensing to evade immune surveillance.

scholarly journals Modulation of Adult Mesenchymal Stem Cells Activity by Toll-Like Receptors: Implications on Therapeutic Potential

2010 ◽  
Vol 2010 ◽  
pp. 1-9 ◽  
Author(s):  
Olga DelaRosa ◽  
Eleuterio Lombardo
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Culture Conditions ◽  
Toll Like Receptors ◽  
Adult Mesenchymal Stem Cells ◽  
Special Relevance ◽  
Tlr Signalling

Mesenchymal stem cells (MSCs) are of special interest as therapeutic agents in the settings of both chronic inflammatory and autoimmune diseases. Toll-like receptors (TLR) ligands have been linked with the perpetuation of inflammation in a number of chronic inflammatory diseases due to the permanent exposure of the immune system to TLR-specific stimuli. Therefore, MSCs employed in therapy can be potentially exposed to TLR ligands, which may modulate MSC therapeutic potential in vivo. Recent results demonstrate that MSCs are activated by TLR ligands leading to modulation of the differentiation, migration, proliferation, survival, and immunosuppression capacities. However inconsistent results among authors have been reported suggesting that the source of MSCs, TLR stimuli employed or culture conditions play a role. Notably, activation by TLR ligands has not been reported to modulate the “immunoprivileged” phenotype of MSCs which is of special relevance regarding the use of allogeneic MSC-based therapies. In this review, we discuss the available data on the modulation of MSCs activity through TLR signalling.

Immune and Inflammatory Responses to Stroke: Good Or Bad?

2008 ◽  
Vol 3 (4) ◽  
pp. 254-265 ◽  
Author(s):  
P. A. McCombe ◽  
S. J. Read
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Immune Responses ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Therapeutic Option ◽  
Regulatory Lymphocytes ◽  
The Brain ◽  
Pro Inflammatory Cytokines

Inflammatory and immune responses play important roles following ischaemic stroke. Inflammatory responses contribute to damage and also contribute to repair. Injury to tissue triggers an immune response. This is initiated through activation of the innate immune system. In stroke there is microglial activation. This is followed by an influx of lymphocytes and macrophages into the brain, triggered by production of pro-inflammatory cytokines. This inflammatory response contributes to further tissue injury. There is also a systemic immune response to stroke, and there is a degree of immunosuppression that may contribute to the stroke patient's risk of infection. This immunosuppressive response may also be protective, with regulatory lymphocytes producing cytokines and growth factors that are neuroprotective. The specific targets of the immune response after stroke are not known, and the details of the immune and inflammatory responses are only partly understood. The role of inflammation and immune responses after stroke is twofold. The immune system may contribute to damage after stroke, but may also contribute to repair processes. The possibility that some of the immune response after stroke may be neuroprotective is exciting and suggests that deliberate enhancement of these responses may be a therapeutic option.

scholarly journals Macrophage Heterogeneity in Kidney Injury and Fibrosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Yi Wen ◽  
Hong-Ru Yan ◽  
Bin Wang ◽  
Bi-Cheng Liu
Keyword(s):  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Tissue Injury ◽  
Kidney Diseases ◽  
Macrophage Polarization ◽  
Kidney Injury ◽  
Kidney Fibrosis ◽  
Functional Changes ◽  
Monocyte Subpopulations ◽  
Macrophage Accumulation

Kidney macrophages are central in kidney disease pathogenesis and have therapeutic potential in preventing tissue injury and fibrosis. Recent studies highlighted that kidney macrophages are notably heterogeneous immune cells that fulfill opposing functions such as clearing deposited pathogens, maintaining immune tolerance, initiating and regulating inflammatory responses, promoting kidney fibrosis, and degrading the extracellular matrix. Macrophage origins can partially explain macrophage heterogeneity in the kidneys. Circulating Ly6C+ monocytes are recruited to inflammatory sites by chemokines, while self-renewed kidney resident macrophages contribute to kidney repair and fibrosis. The proliferation of resident macrophages or infiltrating monocytes provides an alternative explanation of macrophage accumulation after kidney injury. In addition, dynamic Ly6C expression on infiltrating monocytes accompanies functional changes in handling kidney inflammation and fibrosis. Mechanisms underlying kidney macrophage heterogeneity, either by recruiting monocyte subpopulations, regulating macrophage polarization, or impacting distinctive macrophage functions, may help develop macrophage-targeted therapies for kidney diseases.

scholarly journals Roles of Fibroblast Growth Factors and Their Therapeutic Potential in Treatment of Ischemic Stroke

2021 ◽  
Vol 12 ◽  
Author(s):  
Confidence Dordoe ◽  
Keyang Chen ◽  
Wenting Huang ◽  
Jun Chen ◽  
Jian Hu ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Growth Factors ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Fibroblast Growth Factors ◽  
Therapeutic Agents ◽  
Stroke Recovery ◽  
Fibroblast Growth ◽  
Stroke Patients ◽  
The Brain

Stroke is the leading cause of death worldwide, and its treatment remains a challenge. Complex pathological processes are involved in stroke, which causes a reduction in the supply of oxygen and energy to the brain that triggers subsequent cascade events, such as oxidative stress, inflammatory responses and apoptosis, resulting in brain injury. Stroke is a devastating disease for which there are few treatments, but physical rehabilitation can help improve stroke recovery. Although there are very few treatments for stroke patients, the discovery of fibroblast growth factors (FGFs) in mammals has led to the finding that FGFs can effectively treat stroke in animal models. As presented in this review, FGFs play essential roles by functioning as homeostatic factors and controlling cells and hormones involved in metabolism. They could be used as effective therapeutic agents for stroke. In this review, we will discuss the pharmacological actions of FGFs on multiple targets, including their ability to directly promote neuron survival, enhance angiogenesis, protect against blood-brain barrier (BBB) disruption, and regulate microglial modulation, in the treatment of ischemic stroke and their theoretical mechanisms and actions, as well as the therapeutic potential and limitations of FGFs for the clinical treatment of stroke.

Inflammatory outcomes of apoptosis, necrosis and necroptosis

2014 ◽  
Vol 395 (10) ◽  
pp. 1163-1171 ◽  
Author(s):  
Pavel Davidovich ◽  
Conor J. Kearney ◽  
Seamus J. Martin
Keyword(s):  
Cell Death ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Necrotic Cell Death ◽  
Caspase Activation ◽  
Microbial Infection ◽  
Necrotic Cell ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Pro Inflammatory Cytokines

Abstract Microbial infection and tissue injury are well established as the two major drivers of inflammation. However, although it is widely accepted that necrotic cell death can trigger or potentiate inflammation, precisely how this is achieved still remains relatively obscure. Certain molecules, which have been dubbed ‘damage-associated molecular patterns’ (DAMPs) or alarmins, are thought to promote inflammation upon release from necrotic cells. However, the precise nature and relative potency of DAMPs, compared to conventional pro-inflammatory cytokines or pathogen-associated molecular patterns (PAMPs), remains unclear. How different modes of cell death impact on the immune system also requires further clarification. Apoptosis has long been regarded as a non-inflammatory or even anti-inflammatory mode of cell death, but recent studies suggest that this is not always the case. Necroptosis is a programmed form of necrosis that is engaged under certain conditions when caspase activation is blocked. Necroptosis is also regarded as a highly pro-inflammatory mode of cell death but there has been little explicit examination of this issue. Here we discuss the inflammatory implications of necrosis, necroptosis and apoptosis and some of the unresolved questions concerning how dead cells influence inflammatory responses.

scholarly journals Functional remodeling of lysosomes by type I interferon modifies host defense

2020 ◽  
Author(s):  
Hailong Zhang ◽  
Abdelrahim Zoued ◽  
Xu Liu ◽  
Brandon Sit ◽  
Matthew K. Waldor
Keyword(s):  
Host Defense ◽  
Type I Interferon ◽  
Bacterial Pathogen ◽  
Virulence Gene ◽  
Microbial Pathogens ◽  
Type I ◽  
Microbial Infection ◽  
Virulence Gene Expression ◽  
A Genome

SUMMARYOrganelle remodeling is critical for cellular homeostasis, but host factors that control organelle function during microbial infection remain largely uncharacterized. Here, a genome-scale CRISPR/Cas9 screen in intestinal epithelial cells with the prototypical intracellular bacterial pathogen Salmonella led us to discover that type I interferon (IFN-I) remodels lysosomes. Even in the absence of infection, IFN-I signaling modified the localization, acidification, protease activity and proteomic profile of lysosomes. Proteomic and genetic analyses revealed that multiple IFN-I-stimulated genes including Ifitm3, Slc15a3, and Cnp contribute to lysosome acidification. IFN-I-dependent lysosome acidification stimulated intracellular Salmonella virulence gene expression, leading to rupture of the Salmonella-containing vacuole and host cell death. Moreover, IFN-I signaling promoted in vivo Salmonella pathogenesis in the intestinal epithelium, where Salmonella initiates infection. Our findings explain how an intracellular bacterial pathogen co-opts epithelial IFN-I signaling. We propose that IFN-I control of lysosome function broadly impacts host defense against diverse viral and microbial pathogens.

The Therapeutic Potential of 5-HT1B Autoreceptors and Heteroreceptors and 5-HT-Moduline in CNS Disorders

CNS Spectrums ◽  
1998 ◽  
Vol 3 (8) ◽  
pp. 50-58 ◽  
Author(s):  
Hala Sarhan ◽  
Gilles Fillion
Keyword(s):  
Psychiatric Disorders ◽  
Structural Changes ◽  
Therapeutic Potential ◽  
Therapeutic Agents ◽  
Serotonergic System ◽  
Depression And Anxiety ◽  
Brain Areas ◽  
Cns Disorders ◽  
Serotonergic Function ◽  
The Brain

AbstractThe endogenous peptide 5-HT–moduline has been characterized as a novel neuropeptide that binds to 5-HT1B receptors in the brain areas in which it is released. By inducing structural changes in these receptors, this peptide prevents 5-HT binding, thereby desensitizing the receptors and inhibiting serotonergic function. This novel mechanism may help to explain differential effects of the serotonergic system in varying areas of the brain that are innervated by the same or few neurons. In addition, dysfunction or disruption of the 5-HT–moduline system may contribute to psychiatric disorders such as depression and anxiety, and may have important implications for the development of new therapeutic agents for these disorders.

scholarly journals Type I interferon remodels lysosome function and modifies intestinal epithelial defense

2020 ◽  
Vol 117 (47) ◽  
pp. 29862-29871 ◽  
Author(s):  
Hailong Zhang ◽  
Abdelrahim Zoued ◽  
Xu Liu ◽  
Brandon Sit ◽  
Matthew K. Waldor
Keyword(s):  
Bacterial Pathogen ◽  
Virulence Gene ◽  
Microbial Pathogens ◽  
Type I ◽  
Intestinal Epithelial ◽  
Microbial Infection ◽  
Virulence Gene Expression ◽  
Innate Defense ◽  
A Genome

Organelle remodeling is critical for cellular homeostasis, but host factors that control organelle function during microbial infection remain largely uncharacterized. Here, a genome-scale CRISPR/Cas9 screen in intestinal epithelial cells with the prototypical intracellular bacterial pathogenSalmonellaled us to discover that type I IFN (IFN-I) remodels lysosomes. Even in the absence of infection, IFN-I signaling modified the localization, acidification, protease activity, and proteomic profile of lysosomes. Proteomic and genetic analyses revealed that multiple IFN-I–stimulated genes includingIFITM3,SLC15A3, andCNPcontribute to lysosome acidification. IFN-I–dependent lysosome acidification was associated with elevated intracellularSalmonellavirulence gene expression, rupture of theSalmonella-containing vacuole, and host cell death. Moreover, IFN-I signaling promoted in vivoSalmonellapathogenesis in the intestinal epithelium whereSalmonellainitiates infection, indicating that IFN-I signaling can modify innate defense in the epithelial compartment. We propose that IFN-I control of lysosome function broadly impacts host defense against diverse viral and microbial pathogens.

scholarly journals STING inhibitors target the cyclic dinucleotide binding pocket

2021 ◽  
Vol 118 (24) ◽  
pp. e2105465118
Author(s):  
Ze Hong ◽  
Jiahao Mei ◽  
Chenhui Li ◽  
Guohui Bai ◽  
Munire Maimaiti ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Binding Pocket ◽  
Type I Interferons ◽  
Type I ◽  
Microbial Infection ◽  
In Silico Docking ◽  
Cytokine Induction ◽  
Simplex Virus ◽  
Cyclic Dinucleotide

Cytosolic DNA activates cGAS (cytosolic DNA sensor cyclic AMP-GMP synthase)-STING (stimulator of interferon genes) signaling, which triggers interferon and inflammatory responses that help defend against microbial infection and cancer. However, aberrant cytosolic self-DNA in Aicardi–Goutière’s syndrome and constituently active gain-of-function mutations in STING in STING-associated vasculopathy with onset in infancy (SAVI) patients lead to excessive type I interferons and proinflammatory cytokines, which cause difficult-to-treat and sometimes fatal autoimmune disease. Here, in silico docking identified a potent STING antagonist SN-011 that binds with higher affinity to the cyclic dinucleotide (CDN)-binding pocket of STING than endogenous 2′3′-cGAMP. SN-011 locks STING in an open inactive conformation, which inhibits interferon and inflammatory cytokine induction activated by 2′3′-cGAMP, herpes simplex virus type 1 infection, Trex1 deficiency, overexpression of cGAS-STING, or SAVI STING mutants. In Trex1−/− mice, SN-011 was well tolerated, strongly inhibited hallmarks of inflammation and autoimmunity disease, and prevented death. Thus, a specific STING inhibitor that binds to the STING CDN-binding pocket is a promising lead compound for STING-driven disease.

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