An Update on Toll-like Receptor 2, Its Function and Dimerization in Pro- and Anti-Inflammatory Processes

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(15), P. 12464 - 12464

Published: Aug. 5, 2023

While a certain level of inflammation is critical for humans to survive infection and injury, prolonged inflammatory response can have fatal consequences. Pattern recognition Toll-like receptors (TLRs) are key players in the initiation an process. TLR2 one most studied pattern (PRRs) known form heterodimers with either TLR1, TLR4, TLR6, TLR10, allowing it recognize wide range pathogens. Although large number studies been conducted over past decades, there still many unanswered questions regarding mechanisms health disease. In this review, we provide up-to-date overview TLR2, including its homo- heterodimers. Furthermore, will discuss pro- anti-inflammatory properties recent findings prominent TLR2-associated infectious neurodegenerative diseases.

Language: Английский

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Harnessing Epigenetics: Innovative Approaches in Diagnosing and Combating Viral Acute Respiratory Infections

Pathogens, Journal Year: 2025, Volume and Issue: 14(2), P. 129 - 129

Published: Feb. 1, 2025

Acute respiratory infections (ARIs) caused by viruses such as SARS-CoV-2, influenza viruses, and syncytial virus (RSV), pose significant global health challenges, particularly for the elderly immunocompromised individuals. Substantial evidence indicates that acute viral can manipulate host's epigenome through mechanisms like DNA methylation histone modifications part of immune response. These epigenetic alterations persist beyond phase, influencing long-term immunity susceptibility to subsequent infections. Post-infection modulation host may help distinguish infected from uninfected individuals predict disease severity. Understanding these interactions is crucial developing effective treatments preventive strategies ARIs. This review highlights critical role following ARIs in regulating innate defense mechanisms. We discuss implications diagnosing, preventing, treating infections, contributing advancement precision medicine. Recent studies have identified specific changes, hypermethylation interferon-stimulated genes severe COVID-19 cases, which could serve biomarkers early detection progression. Additionally, therapies, including inhibitors methyltransferases deacetylases, show promise modulating response improving patient outcomes. Overall, this provides valuable insights into landscape ARIs, extending traditional genetic perspectives. are essential advancing diagnostic techniques innovative address growing threat emerging causing globally.

Language: Английский

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The single nucleotide polymorphism rs4986790 (c.896A>G) in the gene TLR4 as a protective factor in corona virus disease 2019 (COVID-19)

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 16, 2024

Background and aims Several factors, such as hypertension diabetes mellitus, are known to influence the course of coronavirus disease 2019 (COVID-19). However, there is currently little information on genetic markers that severity COVID-19. In this study, we specifically investigated single nucleotide polymorphism (SNP) rs4986790 in TLR4 gene identify a universal marker for preclinical prediction COVID-19 progression. Methods We analyzed demographics, pre-existing conditions, inflammatory parameters at time hospitalization, genotype outcome comprehensive cohort (N = 1570). performed multivariable analysis investigate impact each factor. Results confirmed younger patient age absence conditions were protective factors against Furthermore, when comparing patients with mild SARS-CoV-2 infection who required hospitalization or intensive care even died due COVID-19, AG/GG was found be factor progression (OR: 0.51, 95% CI: 0.34 - 0.77, p 0.001). addition, demonstrated low levels interleukin-6 (IL-6) procalcitonin (PCT) had favorable effect severity. subsequent analysis, cardiovascular disease, IL-6 PCT, genotypes independent predictors potential reduction severe fatal course. Conclusion identified an additional may serve invariant predictor outcome. The reduced by half risk requiring have able confirm previously upon onset Based these observations, hereby provide another prognostic biomarker could used routine diagnostics predictive prior infection.

Language: Английский

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Gut Microbiota, Inflammatory Bowel Disease, and Cancer: The Role of Guardians of Innate Immunity

Cells, Journal Year: 2023, Volume and Issue: 12(22), P. 2654 - 2654

Published: Nov. 19, 2023

Inflammatory bowel diseases (IBDs) are characterized by a persistent low-grade inflammation that leads to an increased risk of colorectal cancer (CRC) development. Several factors implicated in this pathogenetic pathway, such as innate and adaptive immunity, gut microbiota, environment, xenobiotics. At the mucosa level, complex interplay between immune system microbiota occurs; disequilibrium these two alteration permeability, called ‘leaky gut’. Subsequently, activation several inflammatory pathways composition with proliferation pro-inflammatory bacteria, known ‘pathobionts’, take place, leading further increase inflammation. This narrative review provides overview on principal Pattern Recognition Receptors (PRRs), including Toll-like receptors (TLRs) NOD-like (NLRs), focusing their recognition mechanisms, signaling pathways, contributions responses. We also report genetic polymorphisms TLRs dysregulation NLR can influence regulation contribute development progression disease cancer.

Language: Английский

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SARS-CoV-2: A Glance at the Innate Immune Response Elicited by Infection and Vaccination

Antibodies, Journal Year: 2024, Volume and Issue: 13(1), P. 13 - 13

Published: Feb. 8, 2024

The COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to almost seven million deaths worldwide. SARS-CoV-2 causes infection through respiratory transmission and can occur either without any symptoms or with clinical manifestations which be mild, severe or, in some cases, even fatal. Innate immunity provides the initial defense against virus sensing pathogen-associated molecular patterns triggering signaling pathways that activate antiviral inflammatory responses, limit viral replication help identification removal of infected cells. However, temporally dysregulated excessive activation innate immune response is deleterious for host associates COVID-19. In addition its defensive role, pivotal priming adaptive polarizing effector function. This capacity relevant context both natural vaccination. Here, we provide an overview current knowledge responses

Language: Английский

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Special Issue “The Role of Toll-Like Receptors (TLRs) in Infection and Inflammation 2.0”

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(17), P. 9709 - 9709

Published: Sept. 7, 2024

Toll-like receptors (TLRs) are key players in the innate immune system, host’ first-line defense against pathogens [...]

Language: Английский

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Positive feedback loop involving AMPK and CLYBL acetylation links metabolic rewiring and inflammatory responses

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 25, 2025

Metabolic rewiring underlies effective macrophages defense to respond disease microenvironment. However, the underlying mechanisms driving metabolic enhance macrophage effector functions remain unclear. Here, we demonstrated that reprogramming in inflammatory depended on acetylation of CLYBL, a citramalyl-CoA lyase, at lysine 154 (K154), and blocking CLYBL-K154 restricted release pro-inflammatory factors. Mechanistically, found crucial AMPK-CLYBL positive feedback loop, triggered by toll-like receptors (TLRs), involving AMPK hypophosphorylation CLYBL hyperacetylation. The deacetylase enzyme SIRT2 acted as bridge between phosphorylation acetylation, thereby regulating polarization cytokines. Furthermore, hypoacetylation decreased monocyte infiltration, alleviating cardiac remodeling. These findings suggest loop serves switch response inhibiting may offer promising therapeutic strategy for response-related disorders.

Language: Английский

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TNF/IFN-γ Co-Signaling Induces Differential Cellular Activation in COVID-19 Patients: Implications for Patient Outcomes

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 1139 - 1139

Published: Jan. 28, 2025

TNF and IFN-γ are key proinflammatory cytokines implicated in the pathophysiology of COVID-19. Toll-like receptor (TLR)7 TLR8 known to recognize SARS-CoV-2 induce production. However, it is unclear whether levels altered through TLR-dependent pathways these mediate disease severity during This study aimed investigate association between TNF/IFN-γ immune cell activation understand their role better. We enrolled 150 COVID-19 patients, who were classified by systemic (high (H) or normal–low (N-L)) as TNFHIFNγH, TNFHIFNγN-L, TNFN-LIFNγH, TNFN-LIFNγN-L. Compared patients with TNFN-LIFNγN-L, TNFHIFNγH had high pro- anti-inflammatory cytotoxic molecules, T cells monocytes expressed 1 (TNFR1). Patients presented SNP rs3853839 TLR7 increased MYD88, NFκB, IRF7 (TLR signaling), FADD, TRADD (TNFR1 signaling). Moreover, critical observed four groups, but TNFHIFNγN-L most required invasive mechanical ventilation. concluded that associated hyperactive cells, whereas normal/low hypoactivity, suggesting a model explain may be mediated different depending on levels. These findings highlight potential for exploring modulation therapeutic strategy severe

Language: Английский

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Cyclophilin–CD147 interaction enables SARS-CoV-2 infection of human monocytes and their activation via Toll-like receptors 7 and 8

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 3, 2025

Monocytes and macrophages, as important constituents of the innate immune system, are equipped with multiple Toll-like-receptors (TLRs) to recognize invading pathogens, such SARS-CoV-2, mount an antiviral response. Nevertheless, their uncontrolled activation can lead hyperinflammation seen in severe COVID-19. Surprisingly, we observed that recombinant SARS-CoV-2 Spike (S) Nucleocapsid (N) proteins triggered only a weak proinflammatory response human peripheral blood monocytes. By employing THP-1 Jurkat NF-κB::eGFP reporter cell lines expressing specific TLRs, various TLR ligands blocking antibodies, determined surface including TLR2/1, TLR2/6 TLR4 do not play major role sensing. However, monocytes potently activated by replication-competent correlates viral uptake is monocytes, but lymphocytes. We show monocyte involves two distinct steps. Firstly, infects process independent S protein prime receptor angiotensin-converting enzyme 2. Instead, alternative CD147, which highly expressed on recognizes its well-known interaction partners cyclophilins A B incorporated into virions. Secondly, upon via cyclophilin-CD147 interaction, be inhibited CD147 antibodies or competition cyclophilin B, RNA recognized TLR7/8 endosomes, leading upregulation tumor necrosis factor (TNF), interleukin (IL)-1β IL-6, comprising core hyperinflammatory signature. Taken together, our data reveal novel mechanism how sense suggest targeting axis might beneficial alleviate overt myeloid-driven inflammation infection.

Language: Английский

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Dissecting the COVID‐19 Immune Response: Unraveling the Pathways of Innate Sensing and Response to SARS‐CoV‐2 Structural Proteins

Journal of Molecular Recognition, Journal Year: 2025, Volume and Issue: 38(2)

Published: Feb. 5, 2025

ABSTRACT Severe acute respiratory syndrome coronavirus (SARS‐CoV), the virus responsible for COVID‐19, interacts with host immune system through complex mechanisms that significantly influence disease outcomes, affecting both innate and adaptive immunity. These interactions are crucial in determining disease's severity host's ability to clear virus. Given virus's substantial socioeconomic impact, high morbidity mortality rates, public health importance, understanding these is essential. This article examines diverse responses triggered by SARS‐CoV‐2's structural proteins, including spike (S), membrane (M), envelope (E), nucleocapsid (N) along nonstructural proteins (NSPs) open reading frames. play pivotal roles modulation, facilitating viral replication, evading detection, contributing severe inflammatory such as cytokine storms distress (ARDS). The employs strategies like suppressing type I interferon production disrupting key antiviral pathways, MAVS, OAS‐RNase‐L, PKR. study also explores pathways govern activation suppression of throughout COVID‐19. By analyzing sensing receptors initiated upon recognizing SARS‐CoV‐2 this review elucidates associated response Understanding offers valuable insights therapeutic interventions informs strategies, a deeper COVID‐19 immunopathogenesis.

Language: Английский

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