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Emerging roles of microRNAs in the regulation of Toll-like receptor (TLR)-signaling.

ABSTRACT: Toll-like receptors (TLRs) are evolutionarily conserved molecules that detect exogenous and endogenous molecular patterns and trigger both the innate and adaptive immune systems to initiate a pathogen-specific immune response and eliminate the threat. However, sustained, or prolonged activation of the immune system disrupts immunological homeostasis and leads to chronic or acute inflammatory diseases. MicroRNAs (miRNAs) can intervene in the initiation and modulation of the complex immunoregulatory networks via regulating the expression of TLRs and multiple components of TLR-signaling pathways including signaling proteins, transcription factors, and cytokines. Moreover, the aberrant expression of TLRs can induce the expression of several miRNAs which in turn regulate the expression of TLR signaling components and TLR-induced cytokines. The present review aims to highlight the emerging roles of miRNA in the regulation of TLR signaling, the interaction between the miRNAs and TLRs, and their implication in inflammatory diseases.

SUBMITTER: Banerjee S

PROVIDER: S-EPMC9550351 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Emerging roles of microRNAs in the regulation of Toll-like receptor (TLR)-signaling.

Banerjee Saswati S Thompson Winston E WE Chowdhury Indrajit I

Frontiers in bioscience (Landmark edition) 20210101 4

Toll-like receptors (TLRs) are evolutionarily conserved molecules that detect exogenous and endogenous molecular patterns and trigger both the innate and adaptive immune systems to initiate a pathogen-specific immune response and eliminate the threat. However, sustained, or prolonged activation of the immune system disrupts immunological homeostasis and leads to chronic or acute inflammatory diseases. MicroRNAs (miRNAs) can intervene in the initiation and modulation of the complex immunoregulato ...[more]

PMID: 33049693

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Project description:ObjectiveThrombocytopenia is associated with many viral infections suggesting virions interact with and affect platelets. Consistently, viral particles are seen inside platelets, and platelet activation markers are detected in viremic patients. In this article, we sought mechanistic insights into these virion/platelet interactions by examining how platelets endocytose, traffic, and are activated by a model virion. Approach and Results: Using fluorescently tagged HIV-1 pseudovirions, 3-dimensional structured illumination microscopy, and transgenic mouse models, we probed the interactions between platelets and virions. Mouse platelets used known endocytic machinery, that is, dynamin, VAMP (vesicle-associated membrane protein)-3, and Arf6 (ADP-ribosylation factor 6), to take up and traffic HIV-1 pseudovirions. Endocytosed HIV-1 pseudovirions trafficked through early (Rab4+) and late endosomes (Rab7+), and then to an LC3+ (microtubule-associated protein 1A/1B-light chain 3) compartment. Incubation with virions induced IRAK4 (interleukin 1 receptor-associated kinase 4), Akt (protein kinase B), and IKK (IκB kinase) activation, granule secretion, and platelet-leukocyte aggregate formation. This activation required TLRs (Toll-like receptors) and MyD88 (myeloid differentiation primary response protein 88) but was less extensive and slower than activation with thrombin. In vivo, HIV-1 pseudovirions injection led to virion uptake and platelet activation, as measured by IKK activation, platelet-leukocyte aggregate formation, and mild thrombocytopenia. All were decreased in VAMP-3-/- and, megakaryocyte/platelet-specific, Arf6-/- mice. Similar platelet activation profiles (increased platelet-leukocyte aggregates, plasma platelet factor 4, and phospho-IκBα) were detected in newly diagnosed and antiretroviral therapy-controlled HIV-1+ patients.ConclusionsCollectively, our data provide mechanistic insights into the cell biology of how platelets endocytose and process virions. We propose a mechanism by which platelets sample the circulation and respond to potential pathogens that they take up.

Project description:BackgroundDepressive disorder is a common and serious public health challenge globally. Fructus arctii is a traditional medicinal plant ingredient with diverse pharmacological effects. This study aimed to investigate the therapeutic potential of Fructus arctii in alleviating depressive-like behaviors.Materials and methodsWe established a chronic unpredictable mild stress (CUMS)-induced depression mouse model to assess the antidepressant effects of Fructus arctii. BV2 cells treated with lipopolysaccharide (LPS) were used to mimic neuronal damage. Behavioral tests, including the sucrose preference test, tail-suspension test, and forced swim test, were conducted to evaluate the impact of Fructus arctii on depressive-like behaviors. Let-7e expression was detected by RT-qPCR, and TLR4 signaling pathway activation was evaluated by western blot analysis, which also assessed the inflammatory response by measuring levels of IL-6, IL-1β, MCP-1, TNF-α, and iNOS. Immunohistological analysis was conducted to detect the expression of microglia markers. Luciferase reporter assays verified the interaction between let-7e and TLR4.ResultsFructus arctii administration effectively alleviated depressive-like behaviors induced by CUMS in mice, as evidenced by improved sucrose preference and reduced immobility time in behavioral tests. Mechanistically, Fructus arctii reversed the CUMS-induced downregulation of let-7e and upregulation of TLR4 and MyD88 protein levels in mice hippocampus tissues. In addition, Fructus arctii suppressed microglial activation and reduced the levels of inflammatory factors by upregulating let-7e. Let-7e was verified to bind to TLR4, thereby negatively regulating its expression. TLR4 overexpression reversed the suppressive effect of let-7e upregulation on inflammatory reactions and microglial activation. Furthermore, intracerebroventricular injection of let-7e agomiR alleviated depressive-like behavior and inhibited microglial activation in vivo.ConclusionIn summary, Fructus arctii mitigates depression by regulating the let-7e/TLR4/MyD88 pathway, offering new insights into potential depression therapies.

Dataset Information

Emerging roles of microRNAs in the regulation of Toll-like receptor (TLR)-signaling.

Publications

Emerging roles of microRNAs in the regulation of Toll-like receptor (TLR)-signaling.

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