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INTERPLAY BETWEEN NOD1 AND TLR4 RECEPTORS IN MACROPHAGES: NONSYNERGISTIC ACTIVATION OF SIGNALING PATHWAYS RESULTS IN SYNERGISTIC INDUCTION OF PROINFLAMMATORY GENE EXPRESSIONстатья
- Авторы: Budikhina A.S., Murugina N.E., Dagil Y.A., Nikolaeva A.M., Balyasova L.S., Murugin V.V., Pashchenkova Y.G., Pinegin B.V., Pashenkov M.V., Maximchik P.V., Selezneva E.M., Chkadua G.Z.
- Журнал: Journal of Immunology
- Том: 206
- Номер: 9
- Год издания: 2021
- Издательство: American Association of Immunologists
- Местоположение издательства: United States
- Первая страница: 2206
- Последняя страница: 2220
- DOI: 10.4049/jimmunol.2000692
- Аннотация: Interactions between pattern-recognition receptors shape innate immune responses to pathogens. NOD1 and TLR4 aresynergistically interacting receptors playing a pivotal role in the recognition of Gram-negative bacteria. However, mechanisms oftheir cooperation are poorly understood. It is unclear whether synergy is produced at the level of signaling pathways downstreamof NOD1 and TLR4 or at more distal levels such as gene transcription. We analyzed sequential stages of human macrophageactivation by a combination of NOD1 and TLR4 agonists (N-acetyl-D-muramyl-L-alanyl-D-isoglutamyl-meso-diaminopimelic acid[M-triDAP] and LPS, respectively). We show that events preceding or not requiring activation of transcription, such as activationof signaling kinases, rapid boost of glycolysis, and most importantly, nuclear translocation of NF-kB, are regulatednonsynergistically. However, at the output of the nucleus, the combination of M-triDAP and LPS synergistically inducesexpression of a subset of M-triDAP and LPS-inducible genes, particularly those encoding proinflammatory cytokines (TNF,IL1B, IL6, IL12B, and IL23A). This synergistic response develops between 1 and 4 h of agonist treatment and requires continuoussignaling through NOD1. The synergistically regulated genes have a lower basal expression and higher inducibility at 4 h thanthose regulated nonsynergistically. Both gene subsets include NF-kBinducible genes. Therefore, activation of the NF-kB pathwaydoes not explain synergistic gene induction, implying involvement of other transcription factors. Inhibition of IKKb or p38MAPK lowers agonist-induced TNF mRNA expression but does not abolish synergy. Thus, nonsynergistic activation of NOD1-and TLR4-dependent signaling pathways results in the synergistic induction of a proinflammatory transcriptional program.
- Добавил в систему: Чкадуа Георгий Зурабович