دورية أكاديمية
أعرض في EDS

Inhibition of specific signaling pathways rather than epigenetic silencing of effector genes is the leading mechanism of innate tolerance.

التفاصيل البيبلوغرافية
العنوان: Inhibition of specific signaling pathways rather than epigenetic silencing of effector genes is the leading mechanism of innate tolerance.
المؤلفون: Masyutina AM; Laboratory of Clinical Immunology, National Research Center 'Institute of Immunology' of the Federal Medical-Biological Agency of Russia, Moscow, Russia.; Biological Faculty, Lomonosov Moscow State University, Moscow, Russia., Maximchik PV; Faculty of Fundamental Medicine, Lomonosov Moscow State University, Moscow, Russia., Chkadua GZ; Laboratory of experimental diagnostics and biotherapy of tumors, N.N.Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation, Moscow, Russia., Pashenkov MV; Laboratory of Clinical Immunology, National Research Center 'Institute of Immunology' of the Federal Medical-Biological Agency of Russia, Moscow, Russia.
المصدر: Frontiers in immunology [Front Immunol] 2023 Jan 26; Vol. 14, pp. 1006002. Date of Electronic Publication: 2023 Jan 26 (Print Publication: 2023).
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [Lausanne : Frontiers Research Foundation]
مواضيع طبية MeSH: Lipopolysaccharides*/pharmacology , Lipopolysaccharides*/metabolism , Toll-Like Receptor 4*/metabolism, Humans ; Signal Transduction ; Macrophages/metabolism ; Epigenesis, Genetic ; Receptors, Pattern Recognition/metabolism
مستخلص: Introduction: Macrophages activated through a pattern-recognition receptor (PRR) enter a transient state of tolerance characterized by diminished responsiveness to restimulation of the same receptor. Signaling-based and epigenetic mechanisms are invoked to explain this innate tolerance. However, these two groups of mechanisms should result in different outcomes. The epigenetic scenario (silencing of effector genes) predicts that activation of a PRR should broadly cross-tolerize to agonists of unrelated PRRs, whereas in the signaling-based scenario (inhibition of signaling pathways downstream of specific PRRs), cross-tolerization should occur only between agonists utilizing the same PRR and/or signaling pathway. Also, the so-called non-tolerizeable genes have been described, which acquire distinct epigenetic marks and increased responsiveness to rechallenge with the same agonist. The existence of such genes is well explained by epigenetic mechanisms but difficult to explain solely by signaling mechanisms.
Methods: To evaluate contribution of signaling and epigenetic mechanisms to innate tolerance, we tolerized human macrophages with agonists of TLR4 or NOD1 receptors, which signal via distinct pathways, and assessed responses of tolerized cells to homologous restimulation and to cross-stimulation using different signaling, metabolic and transcriptomic read-outs. We developed a transcriptomics-based approach to distinguish responses to secondary stimulation from continuing responses to primary stimulation.
Results: We found that macrophages tolerized with a NOD1 agonist lack responses to homologous restimulation, whereas LPS-tolerized macrophages partially retain the ability to activate NF-κB pathway upon LPS rechallenge, which allows to sustain low-level expression of a subset of pro-inflammatory genes. Contributing to LPS tolerance is blockade of signaling pathways required for IFN-β production, resulting in 'pseudo-tolerization' of IFN-regulated genes. Many genes in NOD1- or TLR4-tolerized macrophages are upregulated as the result of primary stimulation (due to continuing transcription and/or high mRNA stability), but do not respond to homologous restimulation. Hyperresponsiveness of genes to homologous rechallenge is a rare and inconsistent phenomenon. However, most genes that have become unresponsive to homologous stimuli show unchanged or elevated responses to agonists of PRRs signaling via distinct pathways.
Discussion: Thus, inhibition of specific signaling pathways rather than epigenetic silencing is the dominant mechanism of innate tolerance.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Masyutina, Maximchik, Chkadua and Pashenkov.)
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فهرسة مساهمة: Keywords: NOD1; TLR4; innate immune response; lipopolysaccharide; macrophages; muramyl peptides; tolerance; transcriptome analysis
المشرفين على المادة: 0 (Lipopolysaccharides)
0 (Toll-Like Receptor 4)
0 (Receptors, Pattern Recognition)
تواريخ الأحداث: Date Created: 20230213 Date Completed: 20230214 Latest Revision: 20230217
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC9909295
DOI: 10.3389/fimmu.2023.1006002
PMID: 36776861
قاعدة البيانات: MEDLINE
الوصف
تدمد:1664-3224
DOI:10.3389/fimmu.2023.1006002