Neutrophil Adhesion Is a Prerequisite for Antibody-Mediated Proteolytic Tissue Damage in Experimental Models of Epidermolysis Bullosa Acquisita

Xinhua Yu, Reza Akbarzadeh, Mario Pieper, Thomas Scholzen, Stefanie Gehrig, Carsten Schultz, Detlef Zillikens, Peter König, Frank Petersen

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Although uncontrolled proteolytic activity mediated by activated neutrophils is a major reason for tissue damage, therapeutic approaches using protease inhibitors are inefficient. Here, we investigated the role of the immune complex-induced neutrophil adhesion and protease release in tissue damage. We show both in vitro and in vivo that immune complex-mediated neutrophil adhesion to the target tissue depends on β2 integrins. Without affecting elastase or reactive oxygen species release, blocking of adhesion drastically inhibited tissue damage in an experimental model of autoantibody-mediated skin blistering disease. By using a cell-bound fluorescent resonance energy transfer-based elastase sensor, we detected elastase enzyme activity on the surface of adherent cells resistant to protease inhibitors. Inhibitor resistance was lost by CD18 blockade or deficiency in vitro and in vivo. Immune complex-induced neutrophil adhesion created an enclosed protected space between the cell and its target structure where proteinases and reactive oxygen species can execute their tissue-damaging effect. Because immune complex-induced neutrophil adhesion represents an indispensable step for tissue damage of many diseases, our findings may facilitate the development of strategies for the treatment of such disorders.

Original languageEnglish (US)
Pages (from-to)1990-1998
Number of pages9
JournalJournal of Investigative Dermatology
Volume138
Issue number9
DOIs
StatePublished - Sep 2018

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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