Keratinocyte-Derived Monocyte Chemoattractant Protein 1 (MCP-1): Analysis in a Transgenic Model Demonstrates MCP-1 Can Recruit Dendritic and Langerhans Cells to Skin

Abstract

Chemokines are thought to play a central role in the recruitment and activation of leukocytes during inflammatory responses. Monocyte chemoattractant protein 1 (MCP-1) is a chemokine of the C-C or beta family that is chemotactic in vitro for monocytes, T cells, and basophils. Its excessive production by keratinocytes has been implicated in psoriasis and other skin diseases. To test the in vivo role of MCP-1 in inflammatory skin disease, we undertook the generation of transgenic mice that express murine MCP-1 in the basal layer of epidermis. Despite production of high levels of functional MCP-1 by basal keratinocytes, documented in vivo and in vitro, these mice did not exhibit spontaneous cutaneous inflammation or any other discernible skin pathology. In contrast, elicited inflammation in the skin of these mice differed qualitatively and quantitatively from that observed in non-transgenic controls. Contact hypersensitivity challenge responses in transgenic animals were characterized by an exaggerated lichenoid infiltration of monocytes and T cells. Additional phenotypic characterization of the normal appearing skin in these mice showed that the only spontaneous change was a dramatic increase and redistribution of CD45+, I-A+ cells that assumed a dendritic morphology in situ, including a subset that expressed markers characteristic of Langerhans cells. Taken together, these data indicate that tissue-specific expression of MCP-1 alone is not sufficient to induce an inflammatory response, though its presence can modify inflammatory and immune events initiated by exogenous stimuli. The recruitment of dendritic and Langerhans cells in the absence of inflammation is a previously unknown consequence of cutaneous MCP-1 production in vivo.

Langerhans cells renew in the skin throughout life under steady-state conditions

“…Our finding that MCP gradients play a major role in attracting CCR2 + LC precursors to the skin is consistent with the finding that transgenic overexpression of CCL2 in the basal layer of the epidermis causes an increase in LC frequency 31 . The ability of CCR2 −/− cells, after a 4-8 week delay, to give rise to normal numbers of LCs indicates that other chemokines may also contribute to LC precursor recruitment.…”

“…We tested CCL2 and the related CCR2 ligand, CCL7 (MCP-3), by reversetranscribed-polymerase chain reaction (RT-PCR) using RNA isolated from normal skin or skin that had been exposed to x-irradiation, oil and acetone or UV light. Low amounts of CCL2 and CCL7 transcripts were present in normal skin, which supported published observations 13,30,31 , but they were markedly increased after skin exposure to UV light (Fig. 6).…”

ERK1/2 Regulates Epidermal Chemokine Expression and Skin Inflammation

“…Noteworthily, the pharmacological suppression of ERK1/2 activation produced by an EGFR or a MEK1/2 inhibitor led to an aggravation of the local inflammatory response, with enhanced expression of CCL2 and more numerous CD11b ϩ inflammatory cells, which comprise monocytes, dendritic cells, and neutrophils. The observation that the count of Ly-6G ϩ cells was not increased in the skin treated with the EGFR inhibitor PD168393 or the MEK1/2 inhibitor PD98059 suggests that the higher number of CD11b ϩ cells was essentially due to monocytes and dendritic cells, the principal targets of CCL2 (7,8). In keeping with previous reports in humans (11), we could not detect significant CXCL10 up-regulation during the acute response to irritants.…”

“…In particular, TNF-␣ induces the expression of numerous chemokines, including CCL2/MCP-1, CCL5/RANTES, CCL20/MIP-3␣, CCL27/cutaneous T cell-attracting chemokine, CXCL8/IL-8, and CXCL10/IFN-␥-inducible protein-10 in keratinocytes. Epidermal CCL2 is involved in the early response to injury or irritants, and in T cell-mediated skin disorders (3)(4)(5)(6), and controls the recruitment of monocytes/macrophages, dendritic cells, and T cells (7)(8)(9). Active immigration of T cells, monocytes, as well as neutrophils is also supported by the increased expression of CCL5 (5,6).…”

Monocyte Chemoattractant Protein-1 Selectively Inhibits the Acquisition of CD40 Ligand-Dependent IL-12-Producing Capacity of Monocyte-Derived Dendritic Cells and Modulates Th1 Immune Response

“…MCP-1 is known to play a key role in the accumulation of monocytes in inflammatory sites and may also participate in their constitutive recruitment to peripheral tissues during steady state (14). It is of note that transgenic mice overexpressing MCP-1, under the keratin promoter, show local accumulation of cells with DC morphology in the basal layer of the epidermis (26). This accumulation may result from the direct recruitment of immature DCs or the migration of monocytes followed by local differentiation to DCs.…”