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Signalling platforms that modulate the inflammatory response: new targets for drug development

Nature Reviews Drug Discovery volume 5, pages 864–876 (2006)Cite this article

Key Points

Therapeutic control of inflammation is essential for clinical management of a wide range of high prevalence human diseases including asthma, pulmonary fibrosis, rheumatoid arthritis, periodontitis, Crohn's disease, multiple sclerosis, and an expanding group of auto-inflammatory disorders.

Targeted anti-cytokine therapy is now well established in the management of rheumatoid arthritis and Crohn's disease. Interleukin-1 inhibition appears to be more effective in controlling the manifestations of several auto-inflammatory syndromes, and a number of strategies for interfering with Interleukin-1 signalling are in various stages of development.

However, since available agents have important shortcomings including cost and the lack of predictability in clinical response, both during initiation and maintenance, there is a clear need to develop alternative approaches for inhibiting tumour necrosis factor-α and interleukin-l in a more predictable and cost-effective manner.

The development of small molecules and peptides to target the intracellular signalling pathways of these cytokines including novel anti-inflammatory drug targets based on the clustering of Interleukin-1 receptors into large, multi-protein aggregates, is a promising avenue to pursue.

Interference with receptor aggregation and the functional relationships between receptors and the endoplasmic reticulum effectively abrogates interleukin-1 signalling. The interleukin-1 -generated signal relies on the clustering of receptors into cell adhesion complexes. The assembly of the adhesion complex and its functional connection to signal generation from the endoplasmic reticulum appears to be very dependent on protein tyrosine phosphatases, which are abundant in adhesion complexes, and mutation of which is associated with poorly controlled inflammatory disease.

We suggest that protein tyrosine phosphatases could provide a particularly rich array of targets for the development of small molecular weight peptides for anti-inflammatory drug development.

Abstract

Therapeutically controlling inflammation is essential for the clinical management of many high-prevalence human diseases. Drugs that block the pro-inflammatory cytokines tumour-necrosis factor-α and interleukin-1 (IL-1) can improve outcomes for rheumatoid arthritis and other inflammatory diseases but many patients remain refractory to treatment. Here we explore the need for developing new types of anti-inflammatory drugs and the emergence of novel drug targets based on the clustering of IL-1 receptors into multi-protein aggregates associated with cell adhesions. Interference with receptor aggregation into multi-protein complexes effectively abrogates IL-1 signalling. The exploration of the crucial molecules required for receptor clustering, and therefore signal transduction, offers new targets and scope for anti-inflammatory drug development.

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Figure 1: Sites of action of existing and novel therapeutics for the treatment of inflammation.
Figure 2: Focal adhesion maturation.
Figure 3: Interleukin-1-mediated calcium signalling.

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Acknowledgements

C.A.M., G.P.D and H.E.G. are supported by operating grants from the Canadian Institutes of Health Research.

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Authors and Affiliations

  1. CIHR Group in Matrix Dynamics, University of Toronto, Toronto, M5S 3E2, Canada

    Christopher. A. McCulloch

  2. Toronto General Hospital Research Institute of the University Health Network, and Division of Respirology, Department of Medicine, University of Toronto, Toronto, M5G 2C4, Canada

    Gregory P. Downey

  3. Department of Medicine, University of Manitoba, Winnipeg, Canada

    Hani El-Gabalawy

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  1. Christopher. A. McCulloch
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  2. Gregory P. Downey
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  3. Hani El-Gabalawy
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Correspondence to Christopher. A. McCulloch.

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DATABASES

OMIM

Ankylosing spondylitis

Atherosclerosis

Inflammatory bowel disease

Psoriatic arthritis

Pulmonary fibrosis

Rheumatoid arthritis

Systemic lupus erythematosus

FURTHER INFORMATION

CIHR Group in Matrix Dynamics

Glossary

Innate and acquired immunity

Innate immune responses are activated by pathogens through ligation of Toll-like receptors expressed on the surface of epithelial cells, neutrophils, macrophages, natural killer cells and dendritic cells. Acquired immune responses are highly specific and develop as a result of antigen processing by antigen-presenting cells with subsequent presentation to T cells.

Synovium

The thin layer of connective tissue that forms the inner lining of the joint cavity, which primarily serves to maintain the health of the cartilage.

Acute-phase response

A stereotyped syndrome characterized by the presence of constitutional symptoms such as fatigue and weight loss, elevation in acute-phase proteins such as C-reactive protein and a host of haematological and endocrine changes.

Erosive articular damage

The development of defects in the cartilage and bone adjacent to the joint cavity caused by chronic inflammation of the synovium lining the joint.

Osteoclastogenesis

The process of generating bone-resorbing multinucleated cells from blood-forming precursor cells that is mediated by the sequential action of specific cytokines and growth factors.

Periarticular bone

Bone that is subjacent to the cartilage-covered, load-bearing surfaces of joints.

Inflammasome

A cytosolic complex of proteins that activates caspase 1 to process pro-inflammatory cytokines such as IL-1β and IL-18.

Mesenchymal

The part of the embryonic mesoderm from which connective tissue, bone, cartilage, and the circulatory and lymphatic systems develop.

Protein tyrosine phosphatase

A group of enzymes that remove phosphates from tyrosine residues by hydrolysis.

Focal adhesions

Actin-enriched anchorage sites of adherent cells where there is close apposition of the plasma membrane to the substratum. Focal adhesions are enriched in actin-binding proteins and molecules associated with signalling processes.

Fibroblast

Ubiquitous cells of connective tissue that synthesize and remodel collagen and other extracellular matrix proteins.

Synoviocyte

Cells of soft connective tissues that line the joints and which upon activation can contribute to the degradation of joint tissues.

Chondrocyte

A connective tissue cell that resides in a lacuna within the cartilage matrix.

SH2 (Src homology 2) domain

A conserved sequence of amino acids originally identified in the tyrosine kinase Src that mediates binding to tyrosine residues in target proteins.

Signalosomes

Multimeric protein complexes comprising various signalling molecules that by virtue of their spatial clustering enhance signal transduction138.

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McCulloch, C., Downey, G. & El-Gabalawy, H. Signalling platforms that modulate the inflammatory response: new targets for drug development. Nat Rev Drug Discov 5, 864–876 (2006). https://doi.org/10.1038/nrd2109

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