Receptors in Inflammatory Diseases

Aletta D. Kraneveld, Saskia Braber, Saskia Overbeek, Petra de Kruijf, Pirn Koelink, and Martine J. Smit 

The major events in chronic inflammatory responses are continuous activating tissue resident immune cells and ongoing infiltration of circulating immune cells after which mechanisms of innate and adaptive immunity serve to neutralize and remove the inflammatory stimulus. Chemokines are a subset of cytokines that promote immune cell trafficking and localization to sites of inflammation. 

This chapter discusses the role of chemokines and their receptors in inflammatory diseases of the airways (asthma and COPD), the intestinal tract (inflammatory bowel diseases), the joints (arthritis), the blood vessels (arteriosclerosis), the central nervous system (multiple sclerosis) and the skin (psoriasis). Investigations of receptor-mediated and intracellular signal pathways in chemokine—receptor interactions 

There are many different cell types in the immune system and these cells interact in a complex reaction of signaling and communication to create the overall response. The cells of the immune system derive from two types of cells in the bone marrowy myeloid stem cells and lymphoid stem cells. Myeloid cells give rise to precursor cells of the innate immune system, whereas lymphoid cells generate precursors of cells of the adaptive immune system. Chemokine receptors are found on almost all immune cells. 

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Pease JE, Sabroe I. The role of interleukin-8 and its receptors in inflammatory lung disease implications for therapy. Am J Respir Med 2002 1(1) 19-25. 

Although the physiological function of IL-20 has not been identified, three lines of evidence support a role for IL-20 and its receptor in inflammatory skin diseases such as psoriasis. For example, overexpression of IL-20 in transgenic mice results in neonatal lethality with skin abnormalities similar to those observed in human psoriatic skin (Bll). These include several hallmark characteristics of this multigenic diseases such as increased proliferation of keratinocytes in the basal and the suprabasal layers of the epidermis, aberrant epidermal differentiation, and infiltration of immune cells into the skin (R3). Recombinant IL-20 protein... 

Blocking of chemokine receptors by modifying their corresponding ligands is a promising therapeutic strategy in inflammatory diseases and HIV infection. With the method described here, chemokine derivatives can easily be expressed in a short time and in sufficient amounts. 

The availability of large amounts of raw sequence data, due to public EST collections, and the ability of scientists to access this data, has led to a massive increase in the number of novel proteins identified in silico—that is purely on computational techniques. Nowhere has this been as fruitful as in the chemokine area where there has been an explosive increase in the number of chemokines identified. The challenge now is to piece together the roles that these new chemokines play in routine immunosurveillance and also in inflammatory diseases. This challenge has been taken up in the last year with the identification of ligands for four chemokine receptors previously classified as orphans. In terms of receptor function, we still have a long way to go, since there are still many chemokines for which receptors have not been identified, but at least we have a more complete list of the players as far as the ligands are concerned. 

Sarzi-Puttini P, Atzeni F,Capsoni F, Fubrano E, Doria A Drug-induced lupus erythematosus, Autoimmunity 2005,38 507-518 Vielhauer V, Mayadas TN Functions of TNF and its receptors in renal disease distinct roles in inflammatory tissue injury and immune regulation, Semin Nephrol 2007,27 286-308... 

The possible involvement of CB2 receptors in inflammatory bowel disease has been hypothesised on the basis of recent in vitro studies indeed, cannabinoids exert an inhibitory effect on the expression of tumour necrosis factor (TNF)-a-induced interleukin-release from a human colonic epithelial cell line HT-29, and this effect was reversed by the CB2 receptor antagonist SR144528 (Ihenetu et al. 

Interleukin-1 receptor type II (IL-IRII) is a soluble decoy receptor that binds to IL-ip and prevents it from binding to IL-IRI, which is the signaling receptor. IL-IRII was in development as a potential therapeutic to block the effects of IL-1 in inflammatory diseases such as rheumatoid arthritis (Irikura et al.,... 

Weldon MJ, Maxwell SD. Lymphocytes and macrophage interleukin receptors in inflammatory bowel disease a more selective target for therapy. Gut 1994 35 871-876. 

Chemokines are key players in inflammatory diseases such as rheumatoid arthritis, atherosclerosis, and asthma (reviewed in Koelink et al., 2012) and in the evolution of and metastatic spread of tumors (reviewed in Balkwill, 2012). The strategy of adding chemokine receptor agonists to vaccine adjuvants in order to boost immune reactions is being explored (Bobanga, Petrosiute, Huang, 2013), and the chemokine receptors that are used by HIV as entry coreceptors represent important targets for antiviral prevention and therapy (Kuhmann Hartley, 2008). 

Taken together, the above clearly indicates that cdiemokines and their respective chemokine receptors play an important role in inflammatory diseases. Chemokine receptors can therefore be considered as promising drug targets. 

These data demonstrate the involvement of chemokines and their receptors in inflammatory joint disease. Further information on the role of chemokines and chemokine receptors should come from the use of transgenic or knockout mice in animal models of arthritis. It is clear that blocking the interactions between chemokines and their receptors using antichemokine, antichemokine receptor monoclonal antibodies, or chemokine receptor antagonists may prove to be of therapeutic value in the control inflammatory diseases such as rheumatoid arthritis. 

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