Preclinical Studies Identify Non-Apoptotic Low-Level Caspase-3 as Therapeutic Target in Pemphigus Vulgaris
Authors
Camille Luyet, Katja Schulze, Beyza S. Sayar, Denise Howald, Eliane J. Müller, Arnaud Galichet
Institution
University of Bern
Country
Switzerland
Year
2015
Journal
PLOS one
Abstract
The majority of pemphigus vulgaris (PV) patients suffer from a live-threatening loss of intercellular
adhesion between keratinocytes (acantholysis). The disease is caused by autoantibodies
that bind to desmosomal cadherins desmoglein (Dsg) 3 or Dsg3 and Dsg1 in mucous
membranes and skin. A currently unresolved controversy in PV is whether apoptosis
is involved in the pathogenic process. The objective of this study was to perform preclinical
studies to investigate apoptotic pathway activation in PV pathogenesis with the goal to assess
its potential for clinical therapy. For this purpose, we investigated mouse and human
skin keratinocyte cultures treated with PV antibodies (the experimental Dsg3 monospecific
antibody AK23 or PV patients IgG), PV mouse models (passive transfer of AK23 or PVIgG
into adult and neonatal mice) as well as PV patients’ biopsies (n=6). A combination of
TUNEL assay, analyses of membrane integrity, early apoptotic markers such as cleaved
poly-ADP-ribose polymerase (PARP) and the collapse of actin cytoskeleton failed to provide
evidence for apoptosis in PV pathogenesis. However, the in vitro and in vivo PV models,
allowing to monitor progression of lesion formation, revealed an early, transient and
low-level caspase-3 activation. Pharmacological inhibition confirmed the functional implication
of caspase-3 in major events in PV such as shedding of Dsg3, keratin retraction, proliferation
including c-Myc induction, p38MAPK activation and acantholysis. Together, these
data identify low-level caspase-3 activation downstream of disrupted Dsg3 trans- or cisadhesion
as a major event in PV pathogenesis that is non-synonymous with apoptosis and
represents, unlike apoptotic components, a promising target for clinical therapy. At a
broader level, these results posit that an impairment of adhesive functions in concert with
low-level, non-lethal caspase-3 activation can evoke profound cellular changes which may be of relevance for other diseases including cancer.