lewis-x-antigen and Dermatitis

Selectins mediate the initial adhesion of leukocytes to endothelial cells in many contexts of inflammation-dependent leukocyte recruitment. The glycans that contribute to P- and E-selectin counterreceptor activity arise through glycosylation reactions in which the terminal steps are catalyzed by alpha(1,3) fucosyltransferases (FTs). We examined how selectin ligand activities are controlled in eosinophils by characterizing FT expression profiles and regulatory mechanisms in eosinophils isolated from human blood. We found that FT-IV and FT-VII mRNAs were up-regulated by transforming growth factor-beta1, but the FT-IV transcript consistently predominated in eosinophils. To further define the physiological role of FT-IV and FT-VII in expression of eosinophil selectin ligand, we characterized models of dermal eosinophilia in FT-IV- and/or FT-VII-deficient mice in vivo. FT-IV deficiency yielded a significant decrease in eosinophil recruitment to the skin. Likewise, deficiency of FT-VII also yielded a decrease in eosinophil recruitment. Eosinophil recruitment that remained in the absence of FT-VII was further inhibited by blocking P- or E-selectin and was essentially absent in mice deficient in both enzymes. These observations indicate that FT-IV and FT-VII are both important contributors to selectin-dependent eosinophil recruitment to the skin and may represent therapeutic targets for treating diseases in which eosinophil recruitment contributes to pathophysiology.

Topics: Animals; Blood Cells; Chemokine CCL11; Chemokines, CC; Dermatitis; E-Selectin; Eosinophilia; Eosinophils; Fucosyltransferases; Humans; Lewis X Antigen; Ligands; Mice; Mice, Knockout; N-Acetylglucosaminyltransferases; P-Selectin; RNA, Messenger; Selectins; Skin; Skin Diseases

The role of the inducible L-selectin ligand was studied in complement-dependent acute dermatitis in rats. Although mAbs against typical sialyl Lewis(x) (CSLEX-1 and SNH-3) did not react with skin venules, a sialyl Lewis(x)-like epitope defined by mAb 2H5 (2H5-Ag) was de novo expressed on the endothelial cells of skin venules in the area of inflammation. Expression of 2H5-Ag increased concomitantly with the progression of inflammation. 2H5-Ag was identified at the 75-, 150-, and 180-kDa bands when inflammatory skin tissue was analyzed by Western blotting. In contrast, P- and E-selectins were not detectable. The role of 2H5-Ag in this model was studied in in vitro and in vivo methods. First, 2H5 was i.v. injected 15 min before induction of dermatitis. 2H5 bound to skin venules and significantly reduced the neutrophil infiltration and plasma protein leakage. In contrast, CSLEX-1, mAb ARP2-4 (P-selectin blocker), or mAb ARE-5 (E-selectin blocker) had no effects. Second, adhesion of isolated rat neutrophils to the inflammatory skin section was inhibited significantly when the sections, but not neutrophils, were preincubated with 2H5. Third, fluorescein-labeled normal rat neutrophils were injected into a rat 10 h after induction of dermatitis. The number of labeled neutrophils infiltrated into the inflammatory site was reduced significantly when they were preincubated with HRL-3 (blocking mAb against rat L-selectin), but not with 2H5 or HRL-4 (nonblocking mAb against rat L-selectin). These data show that de novo expressed 2H5-Ag/L-selectin adhesion pathway contributes to the development of acute complement-dependent inflammation in the skin.

Topics: Animals; Dermatitis; Endothelium, Vascular; Epitopes; Female; Inflammation; L-Selectin; Lewis X Antigen; Rats; Rats, Wistar; Skin