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Mitogen-activated protein kinases in innate immunity

Key Points

  • Mitogen-activated protein kinases (MAPKs) in innate immune cells are activated by a range of pattern recognition receptors, of which the best studied are Toll-like receptors (TLRs). TLR ligation induces the formation of a signalling complex that includes IL-1R-associated kinases (IRAKs) and TNFR-associated factor 6 (TRAF6), which is mediated by K63-linked polyubiquitylation. This complex interacts with and activates TGFβ-activated kinase 1 (TAK1), a MAPK kinase kinase (MAP3K) upstream of p38α and Jun N-terminal kinases (JNKs). TAK1 can also activate the IκB kinase (IKK) complex, leading to the activation of the transcription factor nuclear factor-κB and the MAP3K tumour progression locus 2 (TPL2), which is upstream of extracellular signal-regulated kinase 1 (ERK1) and ERK2. Recent genetic evidence, however, has shown that TAK1 is not required for TLR activation of MAPKs in primary macrophages, and the MAP3K involved remains to be identified.

  • MAPK signalling has several of roles in innate immune responses, ranging from the induction of pro-inflammatory mediators, such as cytokines and chemokines, to the activation of anti-inflammatory feedback pathways.

  • MAPKs can activate downstream kinases that have crucial roles in immunity; for example, p38α activates MAPK-activated protein kinase 2 (MK2), which promotes tumour necrosis factor (TNF) production. By contrast, the activation of mitogen- and stress-activated kinases (MSKs) by p38α or by ERK1 and ERK2 results in the increased transcription of the anti-inflammatory cytokines interleukin-10 (IL-10) and IL-1 receptor antagonist (IL-1RA).

  • MAPK signalling induces the expression of dual specificity phosphatases (DUSPs). This establishes a negative feedback loop, in which the DUSPs dephosphorylate and inactivate MAPKs. Genetic studies have shown the crucial role of DUSPs in controlling innate immune responses.

  • Bacterial pathogens have evolved ways to directly target MAPKs to downregulate the host immune response; for example, distinct bacterial proteins have been shown to inhibit MAPK signalling by inactivating MAPK kinase (MKK) enzymes and by activating DUSPs.

  • Small-molecule inhibitors which target MAPK signalling have the potential to function as anti-inflammatory drugs. p38 inhibitors were the first MAPK inhibitors to be developed, but clinical results from using these compounds have been disappointing. As a result, focus in the pharmaceutical industry has shifted to targeting upstream MAP3Ks or downstream kinases, such as MK2.

Abstract

Following pathogen infection or tissue damage, the stimulation of pattern recognition receptors on the cell surface and in the cytoplasm of innate immune cells activates members of each of the major mitogen-activated protein kinase (MAPK) subfamilies — the extracellular signal-regulated kinase (ERK), p38 and Jun N-terminal kinase (JNK) subfamilies. In conjunction with the activation of nuclear factor-κB and interferon-regulatory factor transcription factors, MAPK activation induces the expression of multiple genes that together regulate the inflammatory response. In this Review, we discuss our current knowledge about the regulation and the function of MAPKs in innate immunity, as well as the importance of negative feedback loops in limiting MAPK activity to prevent host tissue damage. We also examine how pathogens have evolved complex mechanisms to manipulate MAPK activation to increase their virulence. Finally, we consider the potential of the pharmacological targeting of MAPK pathways to treat autoimmune and inflammatory diseases.

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Figure 1: MAPK signalling cascades.
Figure 2: Activation of MAPKs.
Figure 3: Negative feedback control of MAPK signalling by p38α.
Figure 4: DUSP regulation of TLR signalling.

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Acknowledgements

J.S.C.A. and S.C.L. are supported by the UK Medical Research Council. The authors would like to thank P. Cohen (University of Dundee, UK), R. Davis (University of Massachusetts, Massachusetts, USA), D. Holden (Imperial College London, UK) and S. Smale (University of California, Los Angeles, California, USA) for their criticisms and advice in the writing of this Review.

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Glossary

Inflammasome

A molecular complex of several proteins that cleaves pro-interleukin-1β (pro-IL-1β) and pro-IL-18 following assembly, thereby producing active IL-1β and IL-18.

E3 ubiquitin ligase

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

Scaffold proteins

Proteins that can bind to multiple proteins in a specific signalling cascade. As a result they can mediate the formation of multiprotein complexes that constitute a signalling pathway. This can help to coordinate the regulation of signalling or to promote the localization of a complex to a specific subcellular location.

K/BxN transgenic mice

A mouse strain formed by crossing non-obese diabetic (NOD)/Lt mice with C57BL/6 KRN T cell receptor-transgenic mice in which T cells recognize a peptide from the self antigen glucose-6-phosphate isomerase (GPI). These mice develop arthritis that is mediated, and transferable, by circulating antibodies against GPI.

Small interfering RNA

(siRNA). Short double-stranded RNAs of 19–23 nucleotides that induce RNA interference, which is a post-transcriptional process that leads to gene silencing in a sequence-specific manner.

Insulin resistance

A condition in which cells in the body fail to respond to changes in insulin levels. As insulin stimulates glucose uptake by muscle and adipose cells while inhibiting glucose production by the liver, this results in elevated levels of blood glucose. Insulin resistance can be an indication of the development of type 2 diabetes.

M1 macrophage

A pro-inflammatory macrophage phenotype that is induced by Toll-like receptor ligands (such as lipopolysaccharide) and interferon-γ. M1 macrophages express, among other things, inducible nitric oxide synthase and nitric oxide.

Glucocorticoids

A group of compounds that belongs to the corticosteroid family. These compounds can either be naturally produced (hormones) or can be synthetic. They affect metabolism and have anti-inflammatory and immunosuppressive effects. Many synthetic glucocorticoids (for example, dexamethasone) are used in clinical medicine as anti-inflammatory drugs.

p300

p300, along with CREB-binding protein (CBP), are co-activator proteins that interact with interferon-regulatory factors and other transcription factors, which promote the recruitment of the RNA polymerase holoenzyme and that allow the transcriptional activation of the interferon (IFN) genes. In addition, p300 and CBP have a histone acetyltransferase activity, which endows these proteins with the capacity to influence chromatin activity by modulating nucleosomal histones.

Caecal puncture and ligation

An experimental model of peritonitis in rodents, in which the caecum is ligated and then punctured to form a small hole. This leads to leakage of intestinal bacteria into the peritoneal cavity and subsequent peritoneal infection.

Local Shwartzman reaction

This is a two-step inflammatory model in which a specific site, normally in the skin, is first sensitized by a local injection of an inflammatory agent such as bacterial endotoxin. A subsequent intravenous injection of the inflammatory agent is then used to invoke the reaction at the sensitized site. Typically this is characterized by haemorrahagic necrosis which develops within 24 hours of the second injection.

NADPH oxidase

An enzyme system that consists of multiple cytosolic and membrane-bound subunits. The complex is assembled in activated neutrophils mainly on the phagolysosomal membrane. NADPH oxidase uses electrons from NADPH to reduce molecular oxygen to form superoxide anions. Superoxide anions are enzymatically converted to hydrogen peroxide, which is converted by myeloperoxidase to hypochloric acid — a highly toxic and microbicidal agent.

Type III secretion systems

Specialized molecular machines present in some bacteria that allow the translocation of bacterial proteins into host cells.

β-elimination

A reaction that results in the loss of atoms or atom groups and in the formation of a new pi bond. The β-elimination of phosphate from phosphotheronine results in the formation of dehydrobutyrine, which contains a CH3–CH side chain with a pi bond that links the side chain to the peptide backbone.

MicroRNA

Single-stranded RNA molecules of approximately 21–23 nucleotides in length that are thought to regulate the expression of other genes.

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Arthur, J., Ley, S. Mitogen-activated protein kinases in innate immunity. Nat Rev Immunol 13, 679–692 (2013). https://doi.org/10.1038/nri3495

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