title: Induction of hyper-adhesion attenuates autoimmune-induced keratinocyte cell-cell detachment and processing of adhesion molecules via mechanisms that involve PKC.
abstract: In confluent keratinocyte monolayers, desmosomal adhesion gradually becomes calcium-independent and this is associated with an increase in the strength of intercellular adhesion (hyper-adhesion). In this study, we investigated the functional and molecular significance of hyper-adhesion in a system challenged by autoimmune sera from patients with Pemphigus Vulgaris (PV), a disease primarily targeting desmosomal adhesion. The results show that keratinocytes with calcium-independent desmosomes are resistant to disruption of intercellular contacts (acantholysis) in experimental PV. Furthermore, both the desmosomal cadherins desmoglein (Dsg) 1 and Dsg3 and the adherens junction protein E-cadherin were decreased in confluent keratinocytes at Day 1, but not in hyper-adhesive cells (Day 6) after incubation with PV serum. Pharmacological induction of the hyper-adhesive state with the PKC inhibitor Go6976 reduced both the acantholysis rate and the processing of cell adhesion molecules induced by PV serum. When the establishment of the hyper-adhesive state was prevented by cell adhesion recognition (CAR) peptides that perturbed desmosomal interactions, Go6976 could still partially attenuate PV acantholysis. Taken together, these data demonstrate that keratinocyte hyper-adhesion decreases the morphological, functional and biochemical dys-cohesive effects of PV serum via mechanisms that involve, at least in part, the function of PKC. This suggests that reinforcing keratinocyte adhesion may be a promising way to inhibit the effects of this most debilitating disorder.
authors.affiliation: Department of Oral and Dental Science, University of Bristol, Lower Maudlin Street, Bristol BS1 2LY, UK. n.cirillo@bristol.ac.uk
authors.forename: Nicola
authors.initials: N
authors.lastname: Cirillo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Lanza
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Prime
mesh_terms: D015551:Autoimmunity; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002478:Cells, Cultured; D051183:Desmoglein 1 / Q000378:metabolism; D051184:Desmoglein 3 / Q000378:metabolism; D015536:Down-Regulation; D005455:Fluorescent Antibody Technique; D005898:Glass / Q000737:chemistry; D006801:Humans; D015603:Keratinocytes / Q000276:immunology*; D008954:Models, Biological; D010392:Pemphigus / Q000097:blood / Q000276:immunology; D011493:Protein Kinase C / Q000378:metabolism*
chemical_list: D015820:Cadherins; D015815:Cell Adhesion Molecules; C495297:DSG1 protein, human; C071894:DSG3 protein, human; D051183:Desmoglein 1; D051184:Desmoglein 3; D011493:Protein Kinase C