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Epidermal expression of intercellular adhesion molecule 1 is not a primary inducer of cutaneous inflammation in
1Division of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
Insights
Elevated intercellular adhesion molecule 1 (ICAM-1) in skin cells did not independently cause inflammation or recruit immune cells in mice. This suggests ICAM-1 requires other factors to initiate cutaneous inflammatory responses.
Area of Science:
- Immunology
- Dermatology
- Molecular Biology
Background:
- Keratinocytes in inflamed skin show increased intercellular adhesion molecule 1 (ICAM-1) expression.
- ICAM-1 is a cytokine-inducible molecule that binds leukocyte integrins LFA-1 and Mac-1.
- Understanding ICAM-1's role in skin inflammation is crucial for immune response research.
Purpose of the Study:
- To investigate the functional consequences of targeted, high-level keratinocyte ICAM-1 expression in vivo.
- To determine if elevated ICAM-1 on keratinocytes alone can induce leukocyte recruitment and skin inflammation.
- To assess the impact of constitutive keratinocyte ICAM-1 on immune cell interactions and inflammatory responses.
Main Methods:
- Generation of transgenic mice with human K14 keratin promoter driving mouse ICAM-1 expression in basal keratinocytes.
- In vitro adhesion assays using cultured transgenic keratinocytes and mouse T cells.
- In vivo assessment of leukocyte infiltration, dermal inflammation, and contact hypersensitivity reactions.
Main Results:
- Transgenic keratinocytes constitutively expressed ICAM-1 at levels exceeding induced levels in wild-type mice.
- In vitro, transgenic keratinocytes facilitated enhanced LFA-1-dependent T cell binding.
- In vivo, high keratinocyte ICAM-1 expression did not increase leukocyte recruitment or cause inflammation, nor did it potentiate hypersensitivity reactions.
Conclusions:
- Elevated ICAM-1 expression on keratinocytes is insufficient to independently trigger leukocyte trafficking or cutaneous inflammation.
- Keratinocyte ICAM-1 requires additional pro-inflammatory signals or mediators to elicit a significant immune response.
- These findings clarify the specific role of keratinocyte-derived ICAM-1 in the context of skin immunity.
Abstract:
Keratinocytes at sites of cutaneous inflammation have increased expression of intercellular adhesion molecule 1 (ICAM-1), a cytokine-inducible adhesion molecule which binds the leukocyte integrins LFA-1 and Mac-1. Transgenic mice were prepared in which the expression of mouse ICAM-1 was targeted to basal keratinocytes by using the human K14 keratin promoter. The level of constitutive expression attained in the transgenic mice exceeded the peak level of ICAM-1 expression induced on nontransgenic mouse keratinocytes in vitro by optimal combinations of interferon gamma and tumor necrosis factor alpha or in vivo by proinflammatory stimuli such as phorbol 12-myristate 13-acetate. In vitro adhesion assays demonstrated that cultured transgenic keratinocytes were superior to normal keratinocytes as a substrate for the LFA-1-dependent binding of mouse T cells, confirming that the transgene-encoded ICAM-1 was expressed in a functional form. However, the high level of constitutive ICAM-1 expression achieved on keratinocytes in vivo in these transgenic mice did not result in additional recruitment of CD45+ leukocytes into transgenic epidermis, nor did it elicit dermal inflammation. Keratinocyte ICAM-1 expression also did not potentiate contact-hypersensitivity reactions to epicutaneous application of haptens. The absence of a spontaneous phenotype in these transgenic mice was not the result of increased levels of soluble ICAM-1, since serum levels of soluble ICAM-1 were equal in transgenic mice and controls. We conclude that elevated ICAM-1 expression on keratinocytes cannot act independently to influence leukocyte trafficking and elicit cutaneous inflammation.