Adhesion Molecules in Skin - Adhesion Molecules - page 287

with the endothelial surface. h is allows them to sample the local endothelial
surface for chemoattractant compounds and to form i rm adhesions if activated.
h e chemokines are a multigene family of chemoattractant compounds that bind
to transmembrane receptors expressed on leukocytes. Chemokines and their
receptors are the most heterogeneous group of molecules involved in leukocyte
recruitment, with more than 50 chemokines and 19 chemokine receptors described.
h e specii c pattern of chemokines and chemoattractant molecules produced
at an anatomical site is inl uenced by the local cytokine milieu, which is in turn
determined by the type of tissue and the mechanism of activation (e.g., pathogen
invasion, thermal burn, irritant exposure). Chemokines are transported to the
endothelial luminal surface, where they bind to proteoglycans for presentation to
rolling cells. Chemokine binding to a suitable receptor activates an intracellular
signaling cascade that results in upregulation of leukocyte integrin avidity and
promotes binding to endothelia. Chemokine receptors on circulating leukocytes
are variably expressed, inl uenced by cell lineage, developmental state and degree
of activation. In addition, individual chemokines may bind multiple receptors
and individual receptors may bind multiple chemokines. h is complexity allows
for subtle ef ects resulting from summed signals received from varied sources,
reminiscent of neural networks.
With regard to T cell recruitment to skin, recent investigations have emphasized
the roles of CC-chemokine receptor 4 (CCR4) and CCR10 and their ligands
CCL17 and CCL27, respectively (Campbell et al. 2007, Sigmundsdottir et al.
2007). Virtually all CLA+ T cells observed in normal or inl amed skin express
CCR4, and CCL17 is constitutively expressed on post-capillary venules in skin
(Chong et al. 2004, Clark et al. 2006). CCR10 is expressed by a smaller subset of
skin homing T cells than CCR4 and has been suggested to have a role in epidermal
positioning of T cells (Soler et al. 2003). CCR6 and CCR8 are also expressed on
populations of skin homing leukocytes and are implicated in cell recruitment to
skin (Fitzhugh et al. 2000, Ebert et al. 2006). As with rolling ligands, the precise
interplay between the various chemoattractant compounds and their receptors
in leukocyte recruitment to resting and inl amed skin is an area of intense
investigation with many details yet to be elucidated.
Adhesion Molecules in Firm Adhesion
Chemokines and chemoattractant compounds upregulate the function of leukocyte
integrins and promote their binding to counter ligands expressed on the vascular
endothelium (Ley et al. 2007). Integrins are relatively unique in that their activity
can be regulated independent of their expression level. h ese interactions result
in i rm (non-rolling) adhesion and are involved in the subsequent transmigration
across the endothelial layer and movement through the surrounding tissue.
Integrins of the β 2 family, including lymphocyte function associated antigen 1