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4 Integrins to Eosinophil Trafficking in Allergic and Nonallergic Inflammatory Reactions in Skin1
Applied Pharmacology, Imperial College School of Medicine at the National Heart and Lung Institute, London, United Kingdom
The role of endothelial selectins in mediating eosinophil
recruitment was assessed using the trafficking of
111In-labeled blood eosinophils in mouse skin. An
intradermal injection of chemoattractants (leukotriene B4,
macrophage inflammatory protein-1
, and eotaxin) resulted in a rapid
accumulation of 111In eosinophils that was reduced 49 to
91% by anti-P-selectin mAb. An anti-E-selectin mAb was
ineffective, although a combined E- and P-selectin blockade resulted in
>95% inhibition of all responses. The accumulation of a pulse of
111In eosinophils at sites of active cutaneous anaphylaxis
(ACA) at 4 to 8 h and at 20 to 24 h after Ag challenge was
completely dependent upon E- and P-selectin in combination, but not in
isolation. In contrast, at 20 to 24 h after Ag challenge in a
delayed-type hypersensitivity (DTH) reaction in skin, 111In
eosinophil accumulation was largely independent of endothelial
selectins, even when L-selectin was also blocked. An
anti-4 integrin mAb significantly reduced
111In eosinophil trafficking in both allergic reactions but
was slightly more effective in the DTH reaction compared with the ACA
reaction. These results show that P-selectin and to a lesser extent
E-selectin mediate eosinophil recruitment in skin in acute inflammatory
reactions. In allergic, late-onset inflammatory reactions, neither P-
nor E-selectin alone are sufficient to mediate eosinophil accumulation;
when combined, they are essential for trafficking in ACA but are less
important in the DTH reaction. Whether 4 integrin-based
strategies will be more effective than selectin-based strategies at
inhibiting eosinophil recruitment in human disease remains to be
determined.
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