The CX3CL1–CX3CR1 system and psoriasis Introduction Psoriasis is a chronic inflammatory dermatosis that affects approximately 2% of the UK popu- lation (1). Typical of complex diseases, develop- ment of psoriasis relies not only on exogenous environmental stimuli, but also on inherited factors (2). The disease is thought to manifest as a consequence of an inappropriate immune response against currently unknown causal agents, of self (e.g. autoantigen) or non-self (e.g. bacteria) origin, whereupon leucocyte recruit- ment and activation at the site of the developing cutaneous lesion perpetuates the disease (3). CX3CL1 (formerly known as fractalkine) and its receptor, CX3CR1 (4) represent plausible pathogenic genes in psoriasis. Both genes map to genomic regions that have been linked previ- ously to psoriasis (5,6), play a role in leucocyte extravasation and modulate the actions of immuno-competent cells in infectious and inflammatory disease (7). Expressed in a num- ber of organs, including skin, tonsil, brain and kidney (8), CX3CL1 can exist in two forms: membrane-anchored or a shed 95-kDa soluble glycoprotein (4). The soluble form is chemotac- tic to natural killer (NK) cells, T cells and monocytes, whereas the membrane-anchored form promotes strong intercellular adhesion of leucocytes via CX3CR1 (9). CX3CL1-induced redistribution of CX3CR1- positive inflammatory leucocytes has been implicated in the development of a number of diseases which have shared characteristics with psoriasis, including rheumatoid arthritis (10) and cardiovascular disease (CVD) (11). More- over, in CVD the chemokine receptor mutation CX3CR1-M280 (amino acid position 280) is reported to confer an impaired adhesive func- tion that correlates with protection from disease development (11). Expression of CX3CL1 and CX3CR1 is ele- vated in plaques of psoriasis when compared with normal skin (4,8). This observation impli- cates a role for CX3CL1/CX3CR1 in the extravasation of leucocytes that occurs both Plant D, Young HS, Watson REB, Worthington J, Griffiths CEM. The CX3CL1–CX3CR1 system and psoriasis. Exp Dermatol 2006: 15: 900–903. Ó 2006 The Authors. Journal compilation Ó 2006 Blackwell Munksgaard. Abstract: CX3CL1 is a chemoattractant and adhesion molecule that induces the redistribution of CX3CR1-positive inflammatory leuco- cytes to sites of inflammation. As a consequence of their increased expression in plaques of psoriasis, and location within genomic regions previously linked to this disease, CX3CL1, and its receptor CX3CR1, represent attractive positional and functional ‘psoriasis susceptibility genes’. To investigate the CX3CL1–CX3CR1 system in psoriasis, eight single nucleotide polymorphisms (SNPs) in CX3CL1 and two SNPs in CX3CR1 were genotyped in 281 psoriasis patients and 184 unrelated controls. Allele, genotype and estimated haplotype frequencies were then compared between experimental groups. Allele frequency differences between healthy volunteers and psoriasis patients revealed associations with two CX3CR1 SNPs (hCV11578468, P ¼ 0.03 and c_5687_1, P ¼ 0.04). No associations were observed between CX3CL1 SNPs and psoriasis. These results support a role for the CX3CL1–CX3CR1 system in the pathogenesis of psoriasis and iden- tify SNPs within the chemokine receptors that are associated with the disease. Darren Plant 1,2 , Helen S. Young 2 , Rachel E. B. Watson 2 , Jane Worthington 1 and Christopher E. M. Griffiths 2 1 Arc Epidemiology Unit, The University of Manchester, Manchester, UK; 2 The Dermatological Sciences Research Group, The University of Manchester, Manchester, UK Key words: cardiovascular disease – CX3CL1 – CX3CR1 – psoriasis – single nucleotide polymorphism Dr D. Plant Arc Epidemiology Unit The University of Manchester Manchester M13 9PT UK Tel.: +44(0)161 275 1673 Fax: +44(0)161 275 5037 E-mail: dplant@fleming.gr/ darren.plant@hotmail.com Accepted for publication 28 June 2006 900 Experimental Dermatology 2006: 15: 900–903 Blackwell Munksgaard . Printed in Singapore doi: 10.1111/j.1600-0625.2006.00486.x Copyright Ó 2006 The Authors. Journal compilation Ó 2006 Blackwell Munksgaard Experimental Dermatology ISSN 0906-6705