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An investigation of the in vivo expression and function of the D6-chemokine decoy receptor

Reference	BB/E013570/1
Principal Investigator / Supervisor	Professor Gerard Graham
Co-Investigators / Co-Supervisors	Professor Robert Nibbs
Institution	University of Glasgow
Department	Inst of Immunology Infection & Inflam
Funding type	Research
Value (£)	400,130
Status	Completed
Type	Research Grant
Start date	26/03/2007
End date	25/09/2010
Duration	42 months

Abstract

The inflammatory response is characterised by initiation, maintenance and resolution phases. Much is known about the leukocytes involved in initiating and maintaining inflammation but the mechanisms involved in switching off the leukocyte recruitment and resolving inflammation are not yet understood. Given the key roles for members of the chemokine family of proinflammatory mediators in recruiting leukocytes to inflamed sites, a mechanism for their removal is likely to be central to the resolution of inflammation. Recently we have been studying the D6 chemokine receptor. This is an atypical chemokine receptor that is characterised by promiscuity of ligand binding. Indeed, D6 can bind all the CC-chemokines involved in leukocyte recruitment to inflamed sites. In addition, D6 does not signal in response to ligand binding and diplays ligand independent constitutive internalisation and recycling. Further in vitro analyses have shown D6 to be capable of internalising inflammatory CC-chemokines and of targetting them for intracellular destruction. This has led us to propose a role for D6 as a scavenging receptor for inflammatory CC chemokines. This is bourne out by studies on D6 null mice which show them to be unable to efficiently remove inflammatory chemokines from inflamed sites. These mice develop exaggerated inflammatory responses. Through the proposed research we hope to extend or understanding of the roles for D6 in the regulation of the in vivo inflammatory response. Specifically we will generate D6-reporter mice using homologous recombination technology. These mice will allow us to examine, in situ, the cell types involved in mediating the in vivo functions of D6 and the dynamics of the expression of D6 in these cells. We will utilise the D6-reporter and D6-null mice to examine roles for D6 in a range of models of cutaneous inflammation. In addition we will examine the regulation of D6 expression and function.

Summary

During evolution, systems have been developed that allow us to respond very rapidly to damage to our tissues or to invading bacteria or other agents. This response involves the cells of our immune system and the most immediate aspect of our immune response is the inflammatory response. During inflammation, white blood cells are recruited into the inflamed sites and they help remove any bacteria or other foreign organisms and also debris from our damaged cells. In addition they help in the processes of repair of the damaged tissues. Thus inflammation is important in a range of responses including wound healing and repair of tissue damage caused by chemical irritants. In many diseases, such as rheumatoid arthritis and psoriasis, inflammation has gone wrong and therefore understanding the inflammatory response is central to our understanding of a number of very prominent diseases. Thus far we know a great deal about the white blood cells that enter inflamed sites and about the roles they play in the inflammatory process. In addition, the signals produced by inflamed tissues that lead to recruitment of the white blood cell are also well characterised. These molecules are called chemokines and they are important for white blood cell navigation to damaged or inflamed tissues. Recently we have become interested in the mechanisms whereby we switch off inflammatory responses as this is a crucial control point in the process. Little is known about the ways in which we do this. We have identified a molecule called D6 which can destroy the chemokines which help the white blood cells get to inflamed sites. We believe therefore that D6 is involved in switching off inflammation by removing the chemokines and therefore blocking the signals for white blood cell recruitment. Indeed mice that do not have D6 are unable to properly switch off inflammation in models of skin inflammation. This suggests that D6 is a fundamentally important regulator of the resolution of the inflammatory response. We now want to try to understand how D6 functions in much more detail. Specifically we propose to generate a mouse model in which D6 is tagged with a label that will allow us to look at exactly where, and when, it is expressed in an intact animal during an inflammatory response. In addition we want to look carefully at the inflamed situations in which D6 works to try to get a broader understanding of the importance of D6 and of its expression in the inflamed context. Finally we want to look at the regulation of D6 expression and function in cells that express D6. We believe that these experiments will be of great importance in improving our understanding of the resolution and control of an inflammatory response.

Committee	Closed Committee - Animal Sciences (AS)
Research Topics	Immunology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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