Secondary Lymphoid Tissue Chemokine (CCL21) Is Upregulated in Allergic Contact Dermatitis

Abstract

Chemokines are important players in the development of allergic contact dermatitis (ACD). The participation of secondary lymphoid tissue chemokine (CCL21) is essential in the induction of the disease due to its expression in lymphatic vessels and in secondary lymphoid organs. Since there is no information about its participation during the effector phase of ACD, we studied this chemokine in patients already diagnosed with ACD, who were challenged with the relevant positive and negative (control) antigens. All patients showed a specific antigen-induced immune response characterized by early expression of inflammatory markers in blood endothelial cells followed by dermal accumulation of mononuclear cells with an important increase in infiltration of CXCR3+ but not of CCR7+ cells. In situ hybridization and immunohistochemistry showed low levels of CCL21 in lymphatic vessels at 2 h, whereas they were significantly increased at 10 and 48 h in all positive patch tests. In contrast, very low expression of this chemokine was observed in skin biopsies from the control site at 48 h. In addition, Langerin+ cells, which were present in dermis from positive patch tests at 2 h, were diminished in number at 10 and 48 h, but a significant number of those cells was still present in dermal areas of the control site at 48 h. We demonstrate for the first time that CCL21, a constitutively expressed chemokine, is strongly upregulated in human lymphatic vessels during a Th1/Tc1 allergic inflammatory response. This can provide the signal required for CCR7+ cells to leave the skin through CCL21-positive lymphatic vessels.

Synergy‐inducing chemokines enhance CCR2 ligand activities on monocytes

“…Even though an in vitro migration assay is far from reproducing the pathological environment during the initial phase of an inflammatory response, it has indicated 300 nM CCL21 as the concentration necessary for inducing a detectable synergism with 1 nM CCL7 on monocytes. CCL21 has been shown to be induced in the skin upon injection of pro-inflammatory cytokines [18] and in contact dermatitis [19], where the concomitant presence of the CCR2 agonists and CCL21 could mediate an elevated recruitment of CCR2 1 cells.…”

“…The CCR2 agonists, CCL2 and CCL7, and the selective CCR7 agonists, CCL19 and CCL21, can be concomitantly expressed in discrete areas in inflamed secondary lymphoid organs [32] and in inflammation in identical regions [19]. We investigated, in vitro, whether the presence of CCL19 or CCL21 would influence the migration of freshly isolated human monocytes, expressing CCR2 but lacking CCR7.…”

“…Most leukocytes express more than one chemokine receptor and, hence, can respond to more than one chemokine. Additionally, a great variety of in situ experiments demonstrated the concomitant expression of chemokines at target sites of leukocyte trafficking and homing [16][17][18][19][20][21].…”

“…Most leukocytes express more than one chemokine receptor and, hence, can respond to more than one chemokine. Additionally, a great variety of in situ experiments demonstrated the concomitant expression of chemokines at target sites of leukocyte trafficking and homing [16][17][18][19][20][21].Many chemokines, apart from being agonistic for their receptors, were shown to act as natural antagonists on one or several receptors in vitro and in vivo [22]. Naturally occurring N-terminal truncations of chemokines have been identified in vivo [23] and numerous enzymes were shown to generate truncations of chemokines that render them less active or inactive [24,25].…”

“…Even though an in vitro migration assay is far from reproducing the pathological environment during the initial phase of an inflammatory response, it has indicated 300 nM CCL21 as the concentration necessary for inducing a detectable synergism with 1 nM CCL7 on monocytes. CCL21 has been shown to be induced in the skin upon injection of pro-inflammatory cytokines [18] and in contact dermatitis [19], where the concomitant presence of the CCR2 agonists and CCL21 could mediate an elevated recruitment of CCR2 1 cells.Extravasation into the underlying tissue involves the degradation of the basal membrane by proteolytic enzymes. We show that the release of degrading enzymes by monocytes is strongly augmented in an environment rich in non-ligand chemokines and could therefore contribute to a faster and more efficient way of recruiting monocytes from the blood stream into lymphoid organs under inflammatory conditions.…”