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  • Review Article
  • Published:

Self-regulation and cross-regulation of pattern-recognition receptor signalling in health and disease

Key Points

  • Several regulators and amplifiers are involved in the fine-tuning of pattern-recognition receptor (PRR) signalling via distinct self-regulation mechanisms.

  • Several distinct modes and new mechanistic insights of cross-regulation of PRR-driven responses have been highlighted by recent research.

  • A complicated interplay between PRRs and/or other immune pathways orchestrates the outcome of host immune defences through synergy, enhancement, suppression, feedback enhancement and feedback suppression.

  • Some epigenetic molecules, post-translational modification enzymes and metabolic mediators regulate innate signalling in an inducible manner, and many of these signalling pathways are involved in immune disorders.

  • Dysfunction of PRR signalling owing to dysregulated regulatory mechanisms is associated with the pathogenesis and prognosis of many immunological diseases.

  • There remain several challenging issues to address, from uncovering the specificity and selectivity of PRR-mediated responses, the assembly of the innate sensor and effector machinery to the targeting of crucial molecules involved in PRR signalling for the control of immunological diseases.

Abstract

In the initiation of innate immune responses against pathogens, pattern-recognition receptors (PRRs) have an essential role in recognizing specific components of microorganisms and triggering responses that eliminate the invading microorganisms. However, inappropriate activation of PRRs can lead to prolonged inflammation and even to autoimmune and inflammatory diseases. Thus, PRR-triggered responses are regulated through the degradation or translocation of the innate receptors themselves and through the involvement of intracellular regulators or amplifiers. In addition, a complex interplay between PRRs and/or other immune pathways finely tunes the outcome of host immune defence responses. In this Review, I describe many of the numerous distinct mechanisms for the self-regulation and cross-regulation of innate immune receptor signalling.

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Figure 1: Signalling pathways and regulators of PRRs.
Figure 2: An integrated model for self-regulation of PRR signalling.
Figure 3: Different mechanistic models for cross-regulation of PRR signalling pathways.
Figure 4: The functions of regulation and dysregulation of PRR signalling in the balanced network of the immune system.

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Acknowledgements

This work was supported by the National Key Basic Research Program of China (2013CB530503) and the National Natural Science Foundation of China (31390431, 81123006).

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Glossary

E3 ubiquitin ligase

An enzyme that is required to attach the molecular tag ubiquitin to proteins. Depending on the position and number of ubiquitin molecules that are attached, the ubiquitin tag can target proteins for degradation in the proteasomal complex, create a scaffold for assembly of signalling complexes, sort them to specific subcellular compartments or modify their biological activity.

Epigenetic modifications

Hereditable regulation of genes achieved without altering the genome sequence, such as through DNA methylation, histone modifications and non-coding RNAs.

DNA methyltransferases

(DNMTs). Enzymes that transfer methyl groups from S-adenosylmethionine to specific adenines or cytosines in genomic DNA. DNA methylation is crucial for the regulation of chromatin remodelling and gene expression.

M2 macrophage

A macrophage that is stimulated by interleukin-4 (IL-4) or IL-13 and that expresses arginase 1, the mannose receptor CD206 and the IL-4 receptor α-chain.

Long non-coding RNAs

(lncRNAs). Non-coding RNAs that are transcribed by RNA polymerase II, have more than 200 nucleotides and have no ability to code protein.

Succinate

Also known as butanedioic acid. The key intermediate in the tricarboxylic acid cycle and also one of the fermentation products of anaerobic metabolism.

Prostaglandin

Cyclopentane ring-containing lipid derived from the metabolism of arachidonic acid by cyclooxygenases and downstream synthase enzymes. Prostaglandins have a diverse range of biological activities and a well-recognized role in inflammation and pain.

Ketone bodies

The three endogenous molecules (acetone, acetoacetic acid and β-hydroxybutyric acid) that are produced from fatty acids in the liver during periods of starvation or carbohydrate restriction, when they serve as energy sources for the body.

Complement system

Three independent pathways can lead to activation of the complement cascade. The classical pathway is activated via C1q binding to immune complexes, the alternative pathway is triggered by direct C3 activation, and the lectin pathway is initiated by the binding of mannose-binding lectin (MBL) to the surface of microorganisms and other activating surfaces.

Pyroptosis

A type of programmed cell death that features rapid rupture of the plasma membrane, depends on caspase 1 activation and is associated with the release of inflammatory cytokines and induction of the host antimicrobial inflammatory response.

Necroptosis

A pro-inflammatory form of caspase-independent cell death. Necroptotic cells display swelling of cellular organelles, cell membrane rupturing and uncontrolled release of cellular contents into the surrounding tissue, ultimately followed by cell death.

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Cao, X. Self-regulation and cross-regulation of pattern-recognition receptor signalling in health and disease. Nat Rev Immunol 16, 35–50 (2016). https://doi.org/10.1038/nri.2015.8

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