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  Interplay between NOD1 and TLR4 Receptors in Macrophages: Nonsynergistic Activation of Signaling Pathways Results in Synergistic Induction of Proinflammatory Gene Expression

Budikhina, A., Murugina, N., Maximchik, P., Dagin, Y., Nikolaeva, A., Balyasova, L., et al. (2021). Interplay between NOD1 and TLR4 Receptors in Macrophages: Nonsynergistic Activation of Signaling Pathways Results in Synergistic Induction of Proinflammatory Gene Expression. The Journal of Immunology, 206(9), 2206-2220. doi:10.4049/jimmunol.2000692.

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 Creators:
Budikhina, AS, Author
Murugina, NE, Author
Maximchik, PV, Author
Dagin, YA, Author
Nikolaeva, AM, Author
Balyasova, LS, Author
Murugin, VV, Author
Selezneva, EV1, Author                 
Pashchenkova, YG, Author
Chkadua , GZ, Author
Pinegin, BV, Author
Pashenkov, MV, Author
Affiliations:
1External Organizations, ou_persistent22              

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 Abstract: Interactions between pattern-recognition receptors shape innate immune responses to pathogens. NOD1 and TLR4 are synergistically interacting receptors playing a pivotal role in the recognition of Gram-negative bacteria. However, mechanisms of their cooperation are poorly understood. It is unclear whether synergy is produced at the level of signaling pathways downstream of NOD1 and TLR4 or at more distal levels such as gene transcription. We analyzed sequential stages of human macrophage activation 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 activation of signaling kinases, rapid boost of glycolysis, and most importantly, nuclear translocation of NF-κB, are regulated nonsynergistically. However, at the output of the nucleus, the combination of M-triDAP and LPS synergistically induces expression 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 continuous signaling through NOD1. The synergistically regulated genes have a lower basal expression and higher inducibility at 4 h than those regulated nonsynergistically. Both gene subsets include NF-κB-inducible genes. Therefore, activation of the NF-κB pathway does not explain synergistic gene induction, implying involvement of other transcription factors. Inhibition of IKKβ or p38 MAPK 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.

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 Dates: 2021-05
 Publication Status: Issued
 Pages: -
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 Identifiers: DOI: 10.4049/jimmunol.2000692
PMID: 33846227
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Title: The Journal of Immunology
  Other : J. Immunol.
Source Genre: Journal
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Publ. Info: Baltimore, U.S.A. : Williams & Wilkins
Pages: - Volume / Issue: 206 (9) Sequence Number: - Start / End Page: 2206 - 2220 Identifier: ISSN: 0022-1767
CoNE: https://pure.mpg.de/cone/journals/resource/954925414915_1