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  • Review Article
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Targeting innate immunity protein kinase signalling in inflammation

Key Points

  • Inflammation is a stereotypical reaction to any form of tissue injury that involves activation of innate immune cells, all kinds of tissue cells as well as adaptive immune cells. The innate immune response is regulated by the concerted activity of many protein kinases in the distinct subsets of cells involved. Lipopolysaccharide and other constituents of bacteria or viruses and damaged tissue cells are recognized by high-affinity receptors that trigger versatile oligomerization of adaptor proteins, causing activation of multiple kinases. Some essential kinases have been identified in canonical inflammatory pathways (interleukin-1 (IL-1) receptor-associated kinases, tumour progression locus 2 (TPL2; also known as mitogen-activated protein kinase (MAPK) kinase kinase 8), transforming growth factor-b-activated kinase 1 (TAK1; also known as MAPK kinase kinase 7), p38α, MAPK and MAPK-activated protein kinases (MKs)) as well as in non-canonical pathways (tyrosine kinase 2 (TYK2), Janus kinase 3 (JAK3), lymphocyte-specific protein tyrosine kinase (LCK) and spleen tyrosine kinase (SYK)), which are crucial modulators of the inflammatory response and innate immunity.

  • Cytokine production is an essential part of the immune response, and kinases involved in regulating the production of master cytokines, such as tumour necrosis factor and IL-1, represent attractive targets for anti-inflammatory therapy. Different MAPK pathways regulate cytokine expression by transcriptional and post-transcriptional mechanisms.

  • Recent insight into the intricate signalling networks and interdependent kinase pathways that determine onset, strength and duration of inflammatory signalling responses comes from different techniques, such as genetic deletion, analysis of the effects of small-molecule inhibition and genome-wide screens.

  • The pace of discovery in signal transduction has been greatly accelerated by the use of a gene-targeting approach in mice and the application of readily established disease models. Modulation of severe or chronic inflammation in knockout mice could ultimately validate numerous kinases as targets for anti-inflammatory therapy, although in some cases the phenotype of animals reveals the restrictions of profound inhibition of certain protein kinases owing to probable side effects. Moreover, tissue-specific knockouts have demonstrated adverse effects of ablating certain protein kinases in different cell types.

  • An increasing number of small-molecule protein kinase inhibitors are being developed and extensively tested for specificity against a panel of human kinases and in animal models of chronic inflammation. New strategies have enabled the development of some efficient, 'tailor-made' inhibitors. Several protein kinase inhibitors have recently entered clinical trials.

  • The p38α MAPK pathway is crucially involved in inflammation and the regulation of cytokine production, and represents an attractive target. However, intrinsic side effects of p38α inhibitors preclude their use as a 'magic bullet' for anti-inflammatory therapy. Inhibition of MKs as well as specific targeting of kinase docking may present future strategies towards targeting the p38α pathway.

  • Detailed understanding of the specific roles of central protein kinases, including their positive and negative control mechanisms, has yielded a wealth of information that can be used, but also needs to be considered as a whole, for the development of next-generation anti-inflammatory drugs. Additional work is needed to define a therapeutic window for kinase inhibitors, to find possible combinations of highly specific inhibitors, and to develop a patient-specific small-molecule inhibitor therapy.

Abstract

Inflammation is an evolutionarily conserved host reaction that is initiated in response to trauma, tissue damage and infection. It leads to changes in tissue homeostasis and blood flow, immune-cell activation and migration, and secretion of cytokines and mediators in a spatio-temporally coordinated manner. Progress in understanding of the mechanisms of the inflammatory response has identified various protein kinases that act as essential signalling components and therefore represent potential therapeutic targets. This article summarizes advances in the identification and validation of such targets, and discusses key issues for the development of small-molecule kinase inhibitors as a new generation of oral anti-inflammatory drugs, including feedback loops, inhibitor specificity and combination therapy.

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Figure 1: Protein kinases and protein kinase-containing signalling complexes involved in the canonical inflammatory response.
Figure 2: Protein kinases and protein kinase-containing signalling complexes involved in the non-canonical inflammatory response.
Figure 3: Regulation of IL-1 β and TNF biosynthesis by protein kinase signalling pathways.
Figure 4: Selected three-dimensional structures of kinase catalytic domain–inhibitor complexes of interest in inflammation.
Figure 5: Where to go from p38α — kinase networks and feedback control.

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Acknowledgements

The work of the authors is supported by Deutsche Forschungsgemeinschaft.

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Protein kinases and protein kinase-containing signalling complexes involved in the inflammatory response. (PDF 479 kb)

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Inflammatory disease models used to evaluate signal transduction components (PDF 297 kb)

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Glossary

Kinome

The subset of genes that code for protein kinases in the genome of an organism.

Pathogen-associated molecular patterns

These are products of bacteria, viruses, fungi and parasites, such as lipopolysaccharide, flagellins, lipoproteins, single-stranded RNA and CpG DNA.

Danger-associated molecular patterns

These can be endogenous host constituents, such as ATP, low K+ levels, DNA, heat shock protein 90, reactive oxygen species, amyloid-β, monosodium urate crystals and calcium pyrophosphate dehydrate, or can be exogenous triggers, such as asbestos, silica crystals, aluminium salts, ultraviolet radiation and skin irritants.

Oxidative burst

The release of reactive oxygen species by granulocytes or macrophages during phagocytosis.

Inflammasome

A multiprotein complex of more than 700 kDa that is responsible for the activation of caspase 1 and caspase 5, leading to the processing and secretion of the pro-inflammatory cytokines IL-1β and IL-18.

ACR 20 response

Improvement in symptoms of rheumatoid arthritis in patients is most often defined by an outcome measure of the American College of Rheumatology (ACR). The ACR 20 is defined as a reduction by 20% or more in the number of tender and swollen joints plus similar improvement in at least three of the following five measures: pain, overall (global) disease assessment by the patient, global disease assessment by the physician, self-assessed physical disability and levels of acute-phase reactants (proteins, the levels of which increase in response to inflammation). Two other outcome measures that are deemed to be more clinically relevant, the ACR 50 (improvement of 50% or more) and the ACR 70 (improvement of 70% or more), are also often reported.

CPK colouring

The CPK colour scheme for chemical elements is based on the colours of the space-filling models developed by Corey, Pauling and Kultun, and is conventionally used by chemists. In this scheme, carbon is represented in grey, oxygen in red, nitrogen in blue, fluoride in green and phosphorous in orange. In addition, in the adjacent figure, hydrophobic amino acid residues of the peptide inhibitors in panels e and g are represented by grey circles and polar amino acid residues by purple circles.

Trans-acting activator of transcription (TAT) peptide

A highly cationic, 11 amino acid peptide derived from the HIV TAT protein that allows covalently coupled molecules to traverse the cell membrane.

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Gaestel, M., Kotlyarov, A. & Kracht, M. Targeting innate immunity protein kinase signalling in inflammation. Nat Rev Drug Discov 8, 480–499 (2009). https://doi.org/10.1038/nrd2829

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