scholarly journals Role of MyD88 in IL-1β and Ethanol Modulation of GABAergic Transmission in the Central Amygdala

2019 ◽  
Vol 9 (12) ◽  
pp. 361 ◽  
Author(s):  
Michal Bajo ◽  
Reesha R. Patel ◽  
David M. Hedges ◽  
Florence P. Varodayan ◽  
Roman Vlkolinsky ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Motor Coordination ◽  
Interleukin 1 ◽  
Adaptor Protein ◽  
Gaba Release ◽  
Primary Response ◽  
Central Amygdala ◽  
Gabaergic Transmission ◽  
Whole Cell Patch Clamp

Myeloid differentiation primary response protein (MyD88) is a critical neuroimmune adaptor protein in TLR (Toll-like receptor) and IL-1R (Interleukin-1 receptor) signaling complexes. These two pro-inflammatory families play an important role in the neurobiology of alcohol use disorder, specifically MyD88 regulates ethanol drinking, ethanol-induced sedation, and ethanol-induced deficits in motor coordination. In this study, we examined the role of MyD88 in mediating the effects of IL-1β and ethanol on GABAergic transmission in the central amygdala (CeA) of male mice using whole-cell patch-clamp recordings in combination with pharmacological (AS-1, a mimetic that prevents MyD88 recruitment by IL-1R) and genetic (Myd88 knockout mice) approaches. We demonstrate through both approaches that IL-1β and ethanol’s modulatory effects at CeA GABA synapses are not dependent on MyD88. Myd88 knockout potentiated IL-1β’s actions in reducing postsynaptic GABAA receptor function. Pharmacological inhibition of MyD88 modulates IL-1β’s action at CeA GABA synapses similar to Myd88 knockout mice. Additionally, ethanol-induced CeA GABA release was greater in Myd88 knockout mice compared to wildtype controls. Thus, MyD88 is not essential to IL-1β or ethanol regulation of CeA GABA synapses but plays a role in modulating the magnitude of their effects, which may be a potential mechanism by which it regulates ethanol-related behaviors.

scholarly journals Epac1 and Glycyrrhizin Both Inhibit HMGB1 Levels to Reduce Diabetes-Induced Neuronal and Vascular Damage in the Mouse Retina

2019 ◽  
Vol 8 (6) ◽  
pp. 772 ◽  
Author(s):  
Li Liu ◽  
Youde Jiang ◽  
Jena J. Steinle
Keyword(s):  
Inflammatory Mediators ◽  
Knockout Mice ◽  
Interleukin 1 ◽  
High Mobility ◽  
Sirtuin 1 ◽  
Mouse Retina ◽  
Necrosis Factor Alpha ◽  
Diabetic Retina ◽  
Factor Alpha

The role of high mobility group box 1 (HMGB1) in acute diabetic retinal damage has been demonstrated. We recently reported that glycyrrhizin, a HMGB1 inhibitor, protected the diabetic retina against neuronal, vascular, and permeability changes. In this study, we wanted to investigate the role of exchange protein for cAMP 1 (Epac1) on HMGB1 and the actions of glycyrrhizin. Using endothelial cell specific knockout mice for Epac1, we made some mice diabetic using streptozotocin, and treated some with glycyrrhizin for up to 6 months. We measured permeability, neuronal, and vascular changes in the Epac1 floxed and knockout mice. We also investigated whether Epac1 and glycyrrhizin work synergistically to reduce the retinal inflammatory mediators, tumor necrosis factor alpha (TNFα) and interleukin-1-beta (IL1β), as well as sirtuin 1 (SIRT1) levels. Epac1 and glycyrrhizin reduced inflammatory mediators with synergistic actions. Glycyrrhizin also increased SIRT1 levels in the Epac1 mice. Overall, these studies demonstrate that glycyrrhizin and Epac1 can work together to protect the retina. Finally, glycyrrhizin may regulate HMGB1 through increased SIRT1 actions.

scholarly journals MyD88 Intrinsically Regulates CD4 T-Cell Responses

2008 ◽  
Vol 83 (4) ◽  
pp. 1625-1634 ◽  
Author(s):  
Shenghua Zhou ◽  
Evelyn A. Kurt-Jones ◽  
Anna M. Cerny ◽  
Melvin Chan ◽  
Roderick Terry Bronson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Interleukin 1 ◽  
Adaptor Protein ◽  
T Cell Response ◽  
Microbial Pathogens ◽  
Wasting Disease ◽  
Lcmv Infection

ABSTRACT Myeloid differentiation factor 88 (MyD88) is an essential adaptor protein in the Toll-like receptor-mediated innate signaling pathway, as well as in interleukin-1 receptor (IL-1R) and IL-18R signaling. The importance of MyD88 in the regulation of innate immunity to microbial pathogens has been well demonstrated. However, its role in regulating acquired immunity to viral pathogens and neuropathogenesis is not entirely clear. In the present study, we examine the role of MyD88 in the CD4+ T-cell response following lymphocytic choriomeningitis virus (LCMV) infection. We demonstrate that wild-type (WT) mice developed a CD4+ T-cell-mediated wasting disease after intracranial infection with LCMV. In contrast, MyD88 knockout (KO) mice did not develop wasting disease in response to the same infection. This effect was not the result of MyD88 regulation of IL-1 or IL-18 responses since IL-1R1 KO and IL-18R KO mice were not protected from weight loss. In the absence of MyD88, naïve CD4+ T cells failed to differentiate to LCMV-specific CD4 T cells. We demonstrated that MyD88 KO antigen-presenting cells are capable of activating WT CD4+ T cells. Importantly, when MyD88 KO CD4+ T cells were reconstituted with an MyD88-expressing lentivirus, the rescued CD4+ T cells were able to respond to LCMV infection and support IgG2a antibody production. Overall, these studies reveal a previously unknown role of MyD88-dependent signaling in CD4+ T cells in the regulation of the virus-specific CD4+ T-cell response and in viral infection-induced immunopathology in the central nervous system.

scholarly journals Protective Role of Interleukin-1 in Mycobacterial Infection in IL-1 α/β Double-Knockout Mice

2000 ◽  
Vol 80 (5) ◽  
pp. 759-767 ◽  
Author(s):  
Hiroyuki Yamada ◽  
Satoru Mizumo ◽  
Reiko Horai ◽  
Yoichiro Iwakura ◽  
Isamu Sugawara
Keyword(s):  
Knockout Mice ◽  
Interleukin 1 ◽  
Mycobacterial Infection ◽  
Protective Role ◽  
Double Knockout

scholarly journals Genetic recovery of ErbB4 in adulthood partially restores brain functions in null mice

2018 ◽  
Vol 115 (51) ◽  
pp. 13105-13110 ◽  
Author(s):  
Hongsheng Wang ◽  
Fang Liu ◽  
Wenbing Chen ◽  
Xiangdong Sun ◽  
Wanpeng Cui ◽  
...  
Keyword(s):  
Neural Development ◽  
Critical Role ◽  
Gaba Release ◽  
Brain Disorders ◽  
Gabaergic Transmission ◽  
Brain Functions ◽  
Adult Mice ◽  
Mutant Strains ◽  
And Behavior

Neurotrophic factor NRG1 and its receptor ErbB4 play a role in GABAergic circuit assembly during development. ErbB4 null mice possess fewer interneurons, have decreased GABA release, and show impaired behavior in various paradigms. In addition, NRG1 and ErbB4 have also been implicated in regulating GABAergic transmission and plasticity in matured brains. However, current ErbB4 mutant strains are unable to determine whether phenotypes in adult mutant mice result from abnormal neural development. This important question, a glaring gap in understanding NRG1–ErbB4 function, was addressed by using two strains of mice with temporal control of ErbB4 deletion and expression, respectively. We found that ErbB4 deletion in adult mice impaired behavior and GABA release but had no effect on neuron numbers and morphology. On the other hand, some deficits due to the ErbB4 null mutation during development were alleviated by restoring ErbB4 expression at the adult stage. Together, our results indicate a critical role of NRG1–ErbB4 signaling in GABAergic transmission and behavior in adulthood and suggest that restoring NRG1–ErbB4 signaling at the postdevelopmental stage might benefit relevant brain disorders.

scholarly journals The Role of TLR2, TLR4, and TLR9 in the Pathogenesis of Atherosclerosis

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Mohsin H. K. Roshan ◽  
Amos Tambo ◽  
Nikolai P. Pace
Keyword(s):  
Adaptor Protein ◽  
Arterial Disease ◽  
Primary Response ◽  
Atheromatous Plaque ◽  
Nf Kappa B ◽  
Coronary Arterial Disease ◽  
Inflammatory Conditions ◽  
Inflammatory Processes ◽  
Molecular Patterns

Toll-like receptors (TLRs) are key players in the pathogenesis of inflammatory conditions including coronary arterial disease (CAD). They are expressed by a variety of immune cells where they recognize pathogen-associated molecular patterns (PAMPs). TLRs recruit adaptor molecules, including myeloid differentiation primary response protein (MYD88) and TIRF-related adaptor protein (TRAM), to mediate activation of MAPKs and NF-kappa B pathways. They are associated with the development of CAD through various mechanisms. TLR4 is expressed in lipid-rich and atherosclerotic plaques. In TLR2−/−and TLR4−/−mice, atherosclerosis-associated inflammation was diminished. Moreover, TLR2 and TLR4 may induce expression of Wnt5a in advanced staged atheromatous plaque leading to activation of the inflammatory processes. TLR9 is activated by CpG motifs in nucleic acids and have been implicated in macrophage activation and the uptake of oxLDL from the circulation. Furthermore, TLR9 also stimulates interferon-α(INF-α) secretion and increases cytotoxic activity of CD4+T-cells towards coronary artery tunica media smooth muscle cells. This review outlines the pathophysiological role of TLR2, TLR4, and TLR9 in atherosclerosis, focusing on evidence from animal models of the disease.

scholarly journals Cross-Talk of Atherosclerosis and Ischemic Stroke: Dramatic Role of Neutrophils

2021 ◽  
Vol 8 (2) ◽  
Author(s):  
Abdolreza Esmaeilzadeh ◽  
Maryam Zarerafie ◽  
Azita Mohammadzadeh
Keyword(s):  
Ischemic Stroke ◽  
Cross Talk ◽  
Interleukin 1 ◽  
Primary Response ◽  
Toll Like Receptor 4 ◽  
Inflammatory Microenvironment ◽  
Inflammatory Conditions ◽  
Tnf Α ◽  
Necrosis Factor

Context: Current investigations illustrate the increasing prevalence of atherosclerosis (AS) through the aggravating role of inappropriate lifestyle patterns. Atherosclerosis is the cause of important vascular-related diseases such as ischemic stroke (IS). Understanding AS pathophysiology can help reduce the incidence of AS-mediated diseases like ischemic stroke. Evidence Acquisition: For this narrative review article, we used the five mega databases of PubMed, Google Scholar, Scopus, Springer, and Science Direct. We searched from 2010 Jan to 2020 Dec and based on keywords and inclusion criteria, 77 articles were enrolled. Results: Based on prior articles on atherosclerosis and ischemic stroke pathophysiology, local and systemic inflammation is a vigorous factor in both diseasesIndeed, the fundamental inflammatory pathway involved atherosclerosis, and ischemic stroke is associated with the toll-like receptor 4/myeloid differentiation primary response 88/nuclear factor-kappa B (TLR4/ Myd88/ NF-κB) cascade. The functional paw of these intricate mechanisms are pro-inflammatory mediators, such as interleukin-1 beta (IL-1β), tumor necrosis factor (TNF-α), and interleukin-18 (IL-18) incite inflammation. Besides, the essential structures termed inflammasomes (multi proteins components), and multiplicity of immune and non-immune cells (i.e., neutrophils, monocytes, platelets, and macrophages) are beneficial in the induction of inflammatory microenvironment. Conclusions: Neutrophils could be the most effective cells in the inflammation-based mechanism in IS and AS. It is clarified that neutrophils with the recruitment of own vesicles and granules can afford to amplify inflammatory conditions and be a key cell in AS and IS cross-talk. Therefore, utilizing methods to control neutrophils-mediated mechanisms could be an effective method for the prevention of AS and IS.

scholarly journals Adiponectin Alleviates Diet-induced Inflammation in the Liver by Suppressing MCP-1 Expression and Macrophage Infiltration

2021 ◽  
Author(s):  
Jiyoon Ryu ◽  
Jason T. Hadley ◽  
Zhi Li ◽  
Feng Dong ◽  
Huan Xu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Knockout Mice ◽  
High Fat Diet ◽  
Adaptor Protein ◽  
Macrophage Infiltration ◽  
Hepatic Inflammation ◽  
High Fat ◽  
Mtorc1 Signaling ◽  
Anti Inflammatory

Adiponectin is an adipokine that exerts insulin sensitizing and anti-inflammatory roles in insulin target tissues including liver. While the insulin sensitizing function of adiponectin has been extensively investigated, the precise mechanism by which adiponectin alleviates diet-induced hepatic inflammation remains elusive. Here, we report that hepatocyte-specific knockout of the adaptor protein APPL2 enhanced adiponectin sensitivity and prevented mice from high fat diet-induced inflammation, insulin resistance, and glucose intolerance, although it caused fatty liver. The improved anti-inflammatory and insulin sensitizing effects in the APPL2 hepatocyte-specific knockout mice were largely reversed by knocking out adiponectin. Mechanistically, hepatocyte APPL2 deficiency enhances adiponectin signaling in the liver, which blocks TNF-a-stimulated MCP-1 expression via inhibiting the mTORC1 signaling pathway, leading to reduced macrophage infiltration and thus reduced inflammation in the liver. Taken together, our study uncovers a mechanism underlying the anti-inflammatory role of adiponectin in the liver and reveals the hepatic APPL2-mTORC1-MCP-1 axis as a potential target for treating overnutrition-induced inflammation in the liver.

IL-1 type I receptor mediates acute phase response to turpentine, but not lipopolysaccharide, in mice

1996 ◽  
Vol 271 (6) ◽  
pp. R1668-R1675 ◽  
Author(s):  
L. R. Leon ◽  
C. A. Conn ◽  
M. Glaccum ◽  
M. J. Kluger
Keyword(s):  
Acute Phase ◽  
Knockout Mice ◽  
Acute Phase Response ◽  
Interleukin 1 ◽  
Body Weight Loss ◽  
Phase Response ◽  
Type I ◽  
Local Inflammation ◽  
Wild Type

This study examined the role of the interleukin-1 (IL-1) type I receptor (IL-1RtI) in the acute phase response (APR) to inflammation in mice. Turpentine (100 microliters/mouse) injected subcutaneously induced fever, lethargy, body weight loss, and anorexia in IL-1RtI wild-type mice. Knockout mice lacking the IL-1RtI were resistant to these effects of turpentine, supporting a role for this receptor in the APR to local inflammation. The intraperitoneal injection of a low (50 micrograms/kg) or high (2.5 mg/kg) dose of lipopolysaccharide (LPS) induced similar APRs in IL-1RtI wild-type and knockout mice. IL-1RtI knockout mice were resistant to the APR induced by peripherally injected murine IL-1 beta, suggesting that it is not the interaction of endogenous IL-1 beta with IL-1RtII that induces an APR to LPS in these mice. We speculate that the absence of IL-1RtI in these knockout mice results in the sensitization of other cytokine pathways to mediate the APR to LPS.

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