VCAM‐1 blockade delays disease onset, reduces disease severity and inflammatory cells in an atopic dermatitis model

Lin Chen,Sanober Amin,Giacomo Maggiolino,Lut Overbergh,Lawrence S Chan,Shao‐Xia Lin

doi:10.1038/icb.2009.107

Abstract

We investigated the roles of critical adhesion molecules ICAM-1 and VCAM-1 in a keratin-14 IL-4 transgenic (Tg) mouse model of atopic dermatitis, the skin lesions of which are characterized by prominent inflammatory cell infiltration, significantly increased mRNAs and proteins of ICAM-1, VCAM-1, E-selectin, P-selectin, L-selectin, and PSGL-1, and significantly increased numbers of dermal vessels expressing these adhesion molecules. We tested the hypotheses that deletion or blockade of these molecules may impede the inflammation by examining the disease progresses in the Tg mice crossed with ICAM-1 knockout mice and Tg mice received anti-VCAM-1 neutralizing antibody. While the findings of the ICAM-1-knockout Tg mice (Tg/ICAM-1−/−) developed skin lesions similar to wide type ICAM-1 Tg mice (Tg/ICAM-1+/+) were surprising, a compensatory mechanism may account for it: the frequency of VCAM-1 ligand, CD49d, on CD3+ T cells in the lesional skin significantly increased in the Tg/ICAM-1−/− mouse, compared to the Tg/ICAM-1+/+ mice. By contrast anti-VCAM-1-treated Tg/ICAM-1−/− or Tg/ICAM-1+/+ mice had significantly delayed onset of skin inflammation compared to isotype antibody-treated groups. Moreover, anti-VCAM-1 significantly reduced the skin inflammation severity in Tg/ICAM-1+/+ mice, accompanied with reduction of mast cell, eosinophil, and CD3+ T-cell infiltration. VCAM-1 is more critical in developing skin inflammation in this model.

Highlights

Atopic dermatitis (AD) is a common, chronically relapsing, debilitating, pruritic, inflammatory skin disorder
Using reverse transcription followed by quantitative real-time Polymerase Chain Reaction (PCR), we found that the mRNAs adhesion molecules in the skin including ICAM-1, VCAM-1, E-selectin, P-selectin, Lselectin, and PSGL-1 mRNAs in the skin of diseased IL-4 epidermal transgenic mice (IL-4 Tg) mice in the late lesion (LL) stage significantly increased, in comparison to that of non-Tg mice
The non-lesional skin showed a further increase of ICAM-1 and VCAM-1 expressions when cultured with medium alone, suggesting that these adhesion molecules are constitutively upregulated in the non-lesional skin of AD possibly because of the cytokines such as IL-4 released by cells in the skin 12

Summary

Introduction

Atopic dermatitis (AD) is a common, chronically relapsing, debilitating, pruritic, inflammatory skin disorder. The major infiltrate of inflammatory cells in the skin lesions of AD are T cells, accompanied by macrophages, mast cells, and eosinophils 2–4. The leukocyte adhesion and extravasation cascade is a multistep process. In the first step that involves leukocyte tethering and rolling on the vessel wall, the transient adhesion interaction is mediated by the selectin family. ICAM and VCAM bind their chemokine activated integrin ligands resulting in firm adhesion and transendothelial migration. In the last step, when cells are attracted to the site of inflammation, for example, skin, the presence of chemokines CCL17 and CCL27, are required 6

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Conclusion