Inducible expression of a CC chemokine liver- and activation-regulated chemokine (LARC)/macrophage inflammatory protein (MIP)-3α/CCL20 by epidermal keratinocytes and its role in atopic dermatitis

Abstract

Liver-and activation-regulated chemokine (LARC)/macrophage inflammatory protein (MIP)-3alpha/CCL20 is a CC chemokine which is constitutively expressed by follicle-associated epithelial cells in the mucosa, and attracts cells expressing CCR6 such as immature dendritic cells and alpha(4)beta(7)(high) intestine-seeking memory T cells. Here, we examine LARC/CCL20 expression in the skin. LARC/CCL20 mRNA and protein were induced in primary human keratinocytes upon stimulation with proinflammatory cytokines such as IL-1alpha and tumor necrosis factor (TNF)-alpha. In mice, intradermal injection of IL-1alpha and TNF-alpha rapidly induced a local accumulation of transcripts for LARC/CCL20 and its receptor CCR6 with a lag of several hours in the latter. In humans, immunostaining of LARC/CCL20 was weak if any in normal skin tissues but strongly augmented in lesional skin tissues with atopic dermatitis. Furthermore, massive infiltration of cells with markers such as CD1a, CD3 or HLA-DR was present in atopic skin lesions. Many infiltrating cells were also found to be CCR6(+) by a newly generated monoclonal anti-CCR6. However, Langerhans cells residing within the epidermis were hardly stained by anti-CCR6 in normal and atopic skin tissues. Furthermore, plasma levels of LARC/CCL20 were found to be elevated in patients with atopic dermatitis. Collectively, our results suggest that epidermal keratinocytes produce LARC/CCL20 upon stimulation with proinflammatory cytokines such as IL-1alpha and TNF-alpha, and attract CCR6-expressing immature dendritic cells and memory/effector T cells into the dermis of inflamed skin such as atopic dermatitis. LARC/CCL20 may not, however, play a major role in homeostatic migration of Langerhans cells into the skin.

IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice

“…It is noteworthy that IFN-γ inhibits MIP-3α production by both TNF-α and IL-1β. IL-1β and/or TNF-α induce MIP-3α in different cell types including keratinocytes, melanocytes, fibroblasts and monocytes [22,23,56], but the inhibitory effect of IFN-γ has not, to our knowledge, been previously described. On the contrary, IFN-γ induces MIP-3α protein expression in human keratinocytes [23], emphasizing the different regulation of chemokine expression in diverse cell types.…”

“…MIP-3α is a CC chemokine which attracts memory T-lymphocytes and dendritic cells expressing the CCR6 receptor [19,20,21]. The expression of MIP-3α is up-regulated in psoriatic skin [22], atopic dermatitis [23] and rheumatoid arthritis [24] and MIP-3α is involved in the amplification of local inflammatory responses in the liver [25]. Fractalkine is the single member of the CX3C family of chemokines.…”

Immune Surveillance and Effector Functions of CCR10+ Skin Homing T Cells

“…We have analyzed a subset of CKRs that are important in memory T cell biology, and addressed which of these CKRs are coexpressed on CCR10 ϩ memory CD4 T cells. The ligands for CCR4 (16 -18), CCR6 (19,20), and CXCR3 (18,21) are found in inflamed skin, and ligands for CCR7 are found in both lymphoid and peripheral tissues (1). Coexpression of different CKRs investigates the potential for cooperative or redundant mechanisms to facilitate T cell entry into peripheral tissues during immune surveillance or during T cell-mediated disease episodes.…”

“…CCR6 is expressed on some CLA ϩ memory CD4 T cells, but is also found on the ␣ 4 ␤ 7 ϩ and a subset of the CLA Ϫ /␣ 4 ␤ 7 Ϫ memory CD4 populations (52). CCR6 and its ligand CCL20/MIP-3␣ are weakly expressed in normal skin, but are up-regulated in psoriatic and AD lesions (19,20), and CCR6 ϩ but not CCR6 Ϫ memory T cells roll and adhere to TNF-activated human dermal microvascular endothelial cells (43) . Figs.…”

Clinical correlations of recent developments in the pathogenesis of atopic dermatitis

“…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.…”