Chemokines are central to the migration of leukocytes around the body, during bothinflammatory and homeostatic conditions. Chemokines mediate their effects by binding tochemokine receptors found on the migrating cell’s surface. Chemokine binding to thechemokine receptor results in signaling, which allows the cell to migrate towards theepicenter of chemokine production.In addition to ‘classical’ chemokine receptors which are involved in leukocyte migration, adiscrete family of chemokine receptors exist which are considered to be ‘atypical’, asbinding to their cognate ligands does not result in classical signaling as detected bycalcium flux assays. One of these atypical chemokine receptors is the chemokinescavengingreceptor D6, which can bind to and internalize at least 14 inflammatory CCchemokines in vitro. In addition, an analysis of D6 function in vivo has shown that D6 isimportant for the resolution of the inflammatory response. D6 KO mice treated withphorbol ester to the shaved dorsal skin developed an inflammatory skin pathology thatresembled the human condition psoriasis in many respects. In contrast, WT mice treatedwith phorbol ester developed a very mild inflammatory response, which quickly resolved.These data suggested that a loss of D6 expression ‘primed’ the mouse to develop apsoriasisform pathology, requiring only minor irritation/trauma to develop the pathology.Similarly, histologically normal (uninvolved) skin from a psoriatic patient has a propensityto developing inflammatory lesions upon minor trauma, and could also be suggested to be‘primed’ for lesion development. Collectively, these data led us to the followinghypothesis,‘A loss of D6 expression in uninvolved psoriatic skin is associated with the developmentof psoriatic lesions’.To test this hypothesis, D6 expression in clinical samples from psoriasis patients wasanalysed. Full thickness biopsies from psoriasis patients were taken from a histologicallynormal site (uninvolved psoriatic skin), in addition to an elliptical biopsy covering the skindirectly adjacent to the psoriatic lesion (peri-lesional psoriatic skin), in addition to thelesion itself (lesional psoriatic skin). D6 expression was analysed in these biopsies byQPCR and immuno-staining. It was observed that D6 expression was significantly elevatedin psoriatic skin compared to healthy control skin. In particular, in uninvolved psoriaticskin D6 was significantly increased compared to healthy control skin, or peri-lesional3psoriatic skin or lesional psoriatic skin. The increase in D6 expression in uninvolvedpsoriatic skin localised to the epidermis and the LVs. A significant increase in PBMC-D6expression was also noted in psoriatic patients compared to healthy control PBMCs. Thesedata suggest that at sites not directly involved in the pathology, D6 is elevated in anattempt to limit inflammation-induced damage.Further immuno-staining showed the inflammatory CC chemokines CCL2 and CCL5 (bothhigh affinity D6-binding ligands) were detected in uninvolved psoriatic epidermis, butwere apparently unable to mediate their function due to the lack of significant leukocyteinfiltration into the tissue. These data gave rise to the idea that D6 in uninvolved psoriaticskin was significantly elevated in an attempt to block the release of inflammatory CCchemokines into the dermis, and subsequent migration of inflammatory leukocytes into thetissue, and the onset of lesion formation. Interestingly, D6 expression on the epidermis wasstrongest towards the lower layers of the epidermis, which suggested a role for epidermal-D6 in ‘barrier function’, preventing the uncontrolled release of inflammatory CCchemokines into the dermis.In addition to inflammatory CC chemokines, a variety of inflammatory cytokines havebeen previously detected in uninvolved psoriatic skin. Several of these cytokines wereshown to increase D6 expression in vitro in this study. Therefore, it is possible thesignificant increase in D6 expression in uninvolved psoriatic skin is partly mediated bycytokine stimulation.A loss of D6 expression was observed when comparing uninvolved psoriatic skin and perilesionalpsoriatic skin. These data suggested that a loss of D6 expression occurs directlybefore the onset of lesion formation. It was also shown in this study that a loss of D6expression could occur after micro-trauma to uninvolved psoriatic skin, which suggests apossible mechanism of how D6 expression is lost in peri-lesional psoriatic skin.To analyze whether the increase in D6 expression in psoriatic skin was disease specific, ora generic response to cutaneous inflammation, D6 expression in eczema skin was studied.It was found that D6 expression in eczema skin is elevated compared to healthy controlskin, but less so compared to psoriatic skin. Collectively these data suggest that increasedD6 expression may be a feature of inflammatory skin diseases.
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