CC Chemokine Ligand 18, An Atopic Dermatitis-Associated and Dendritic Cell-Derived Chemokine, Is Regulated by Staphylococcal Products and Allergen Exposure

Abstract

Atopic dermatitis is a chronic inflammatory skin disease with a steadily increasing prevalence. Exposure to allergens or bacterial superantigens triggers T and dendritic cell (DC) recruitment and induces atopic skin inflammation. In this study, we report that among all known chemokines CCL18/DC-CK1/PARC represents the most highly expressed ligand in atopic dermatitis. Moreover, CCL18 expression is associated with an atopic dermatitis phenotype when compared with other chronic inflammatory skin diseases. DCs either dispersed within the dermis or clustering at sites showing perivascular infiltrates are abundant sources of CCL18. In vitro, microbial products including LPS, peptidoglycan, and mannan, as well as the T cell-derived activation signal CD40L, induced CCL18 in monocytes. In contrast to monocytes, monocyte-derived, interstitial-type, and Langerhans-type DCs showed a constitutive and abundant expression of CCL18. In comparison to Langerhans cells, interstitial-type DCs produced higher constitutive levels of CCL18. In vivo, topical exposure to the relevant allergen or the superantigen staphylococcal enterotoxin B, resulted in a significant induction of CCL18 in atopic dermatitis patients. Furthermore, in nonatopic NiSO4-sensitized individuals, only relevant allergen but not irritant exposure resulted in the induction of CCL18. Taken together, findings of the present study demonstrate that CCL18 is associated with an atopy/allergy skin phenotype, and is expressed at the interface between the environment and the host by cells constantly screening foreign Ags. Its regulation by allergen exposure and microbial products suggests an important role for CCL18 in the initiation and amplification of atopic skin inflammation.

Mature Dendritic Cells Express Functional Thrombin Receptors Triggering Chemotaxis and CCL18/Pulmonary and Activation-Regulated Chemokine Induction

“…Moreover, CCL18 expression is also detected in atherosclerotic lesions (21). In monocytes in vitro its production is induced by LPS and CD40L (53), whereas in iDC it is activated by anti-inflammatory stimuli such as IL-10 or vitamin D 3 (54,55). Since rodents do not have a CCL18 analog, studies on its regulation and function in vivo have been hampered (19).…”

Clinical correlations of recent developments in the pathogenesis of atopic dermatitis

“…However, CCL18 is the most highly expressed ligand specific to AD with levels in the lesional skin reported to be 100 fold higher than CCL17. 115 The regulation of CCL18 by allergen exposure and microbial products suggest a crucial role for this chemokine in the initiation and amplification of atopic skin inflammation. 115,120 Further, CCL1-CCR8 mediated recruitment has been shown to play a role in DC-T cell interactions at the sites of atopic skin inflammation.…”

“…115 The regulation of CCL18 by allergen exposure and microbial products suggest a crucial role for this chemokine in the initiation and amplification of atopic skin inflammation. 115,120 Further, CCL1-CCR8 mediated recruitment has been shown to play a role in DC-T cell interactions at the sites of atopic skin inflammation. Further work will delineate whether targeting these molecules might provide therapeutic benefit.…”

“…70,[106][107][108][109][110][111][112][113][114][115][116][117] CCL27 is a skin specific chemokine made by keratinocytes following induction by TNF-α and IL-1β. 108,118 The CCL27-CCR10 interaction plays an important role in controlling recruitment of memory T cells to the skin 108 though CCR4 has also been reported to play a role in this process, and skin homing CLA+ memory T cells have been shown to express CCR10 and CCR4.…”

Expression and Function of CCL17 in Atopic Dermatitis

“…As further discussed below, CCR4 and CCR10 ligands cooperate in the recruitment of memory T cells to sites of skin inflammation (Mirshahpanah et al, 2008;Reiss et al, 2001). The human chemokine CCL18 is one of the most highly expressed chemokines produced by DC in lesional skin of AD patients but not in psoriasis (Fujita et al, 2011;Gros et al, 2009;Pivarcsi et al, 2004). Pivarcsi et al showed that allergen exposure, as well as staphylococcal products induced its expression in vitro and in vivo.…”