Control of intestinal inflammation by the D6 decoy chemokine receptor

Chemokines are small chemical messengers which play an important role in inflammation and are involved in the diseases caused by excessive or inappropriate inflammation. The body has to control the levels and functions of these important messengers. One way this can be done is by the use of specialised molecules that bind chemokines and destroy them. We have discovered one of these molecules, known as D6, that removes inflammatory chemokines. However, surprisingly, our recent work suggests that D6 may actually have a positive role in intestinal inflammation rather than preventing it. This is associated with increased production of another important chemical messenger of the immune system, interleukin 17. The purpose of this application is to investigate how D6 can control colitis, by finding which cells it is present on in the colon and by examining how D6 controls interleukin 17 in the intestine. We will look at specialised cells known as dendritic cells (DC) which are known to stimulate other cells to make interleukin 17 preferentially. By understanding the links between these different chemical messengers in the intestine, we hope ultimately to assist the development of new treatments for inflammatory diseases

Chemokines are crucial components of host defence against infection and are important for other aspects of immune function, including inflammatory disease and immunoregulation. Chemokines and their receptors thus offer potentially important targets for therapy and immunomodulation. Chemokine production and function is tightly controlled in vivo and one way this is achieved is by scavenger receptors which sequester and destroy chemokines without signalling. One such receptor is D6, which binds at least ten pro-inflammatory CC chemokines, and reduces their bioavailability in vivo. The significance of this level of chemokine regulation is now beginning to emerge, with D6 playing a critical role in resolving cutaneous inflammation. We have recently discovered that D6 knock-out (KO) mice are less susceptible to the induction of colitis by oral administration of dextran sodium sulphate (DSS). This is associated a dramatic increase in production of mucosal IL17, known to be protective in this model. Here, we will investigate how D6 regulation of CC chemokines in the inflamed mucosa modulates production of IL17, and determine in turn how this cytokine modifies intestinal inflammation. To do this we will (i) characterise and localise D6-expressing cells in normal and inflamed colon, using, amongst other approaches, mice that carry a lacZ reporter gene in place of endogenous D6; (ii) explore the effects of D6 gene dose in four distinct models of intestinal inflammation, exploiting D6 KO mice and novel D6 transgenics that allow cre-recombinase inducible expression of D6 in intestinal epithelial cells; (iii) define the role of IL17 in manifesting the colitis-modifying properties of D6 gene dose, gauging its impact on intestinal inflammation and epithelial repair; (iv) determine how D6 gene dose affects the generation of IL17 producing CD4+ T cells (Th17), and the function of mucosal dendritic cells (DCs); (v) determine the responsiveness of Th17 to pro-inflammatory CC chemokines. By dissecting the cellular basis for D6 function and IL17 in intestinal inflammation, these studies will determine how chemokine regulation may contribute to the pathogenesis of inflammatory disease in the gut and other tissues, as well as contributing more generally to the understanding the biological and pathological role of IL17