Signaling Crosstalk Mechanisms That May Fine-Tune Pathogen-Responsive NFκB.

Adewunmi Adelaja,Alexander Hoffmann

doi:10.3389/fimmu.2019.00433

Adewunmi Adelaja, Alexander Hoffmann

Open Access

https://doi.org/10.3389/fimmu.2019.00433

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Abstract

Precise control of inflammatory gene expression is critical for effective host defense without excessive tissue damage. The principal regulator of inflammatory gene expression is nuclear factor kappa B (NFκB), a transcription factor. Nuclear NFκB activity is controlled by IκB proteins, whose stimulus-responsive degradation and re-synthesis provide for transient or dynamic regulation. The IκB-NFκB signaling module receives input signals from a variety of pathogen sensors, such as toll-like receptors (TLRs). The molecular components and mechanisms of NFκB signaling are well-understood and have been reviewed elsewhere in detail. Here we review the molecular mechanisms that mediate cross-regulation of TLR-IκB-NFκB signal transduction by signaling pathways that do not activate NFκB themselves, such as interferon signaling pathways. We distinguish between potential regulatory crosstalk mechanisms that (i) occur proximal to TLRs and thus may have stimulus-specific effects, (ii) affect the core IκB-NFκB signaling module to modulate NFκB activation in response to several stimuli. We review some well-documented examples of molecular crosstalk mechanisms and indicate other potential mechanisms whose physiological roles require further study.

Highlights

NFκB signaling mediates inflammatory and innate immune responses; the signaling components that comprise the core signaling pathway are well-understood and have been amply reviewed, for example by Mitchell et al [1], Leifer and Medvedev [2], Pandey et al [3], and Hayden and Ghosh [4]
This review focuses on the cross-regulation of the toll-like receptors (TLRs)-NFκB signaling axis by type I and II IFNs
The putative mechanism by which SOCS1 inhibits TLR signaling is through ubiquitin-mediated degradation of TIR domain containing adaptor (TIRAP), which recruits myeloid differentiation primary response gene 88 (MyD88) to TLR2 and TLR4 by mitigating the effects of electrostatic repulsion [52]

Summary

Introduction

NFκB signaling mediates inflammatory and innate immune responses; the signaling components that comprise the core signaling pathway are well-understood and have been amply reviewed, for example by Mitchell et al [1], Leifer and Medvedev [2], Pandey et al [3], and Hayden and Ghosh [4]. IFNγ is a well-described crosstalk mediator that enhances NFκB signaling (Figure 3) [20]. The significance of TNF-induced and IFNγinduced upregulation of TLR abundance on NFκB signaling dynamics is unknown. While IFNγ upregulates the expression of TLRs and accessory proteins that promote inflammatory responses, it upregulates negative feedback regulators to maintain homeostasis (Figure 3).

Results

Conclusion