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High mobility group box-1 contributes to anti-myeloperoxidase antibody-induced
glomerular endothelial cell injury through a moesin-dependent route
#MMPMID28587670
Deng H
; Wang C
; Chang DY
; Hu N
; Chen M
; Zhao MH
Arthritis Res Ther
2017[Jun]; 19
(1
): 125
PMID28587670
show ga
BACKGROUND: Our previous study found that circulating and urinary levels of high
mobility group box-1 (HMGB1) were closely associated with disease activity in
patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis
(AAV). Moreover, HMGB1 participates in ANCA-induced neutrophil activation.
Cross-reactivity between moesin and anti-myeloperoxidase (MPO) antibody has been
reported in both human and mouse. The current study investigated whether HMGB1
participated in MPO-ANCA-induced glomerular endothelial cell (GEnC) injury, which
is one of the most important aspects in the pathogenesis of AAV. METHODS: The
effects of HMGB1 on expression of moesin on GEnCs and anti-MPO antibody binding
to GEnCs were measured. MPO expression on GEnCs was explored. The effects of
HMGB1 in MPO-ANCA induced GEnC injury were measured, during which the role of
moesin was explored. Antagonists for various relevant receptors were employed.
RESULTS: Sera from AAV patients at the active stage could mediate GEnC injury,
while this effect could be attenuated by preblocking HMGB1. HMGB1 could increase
the expression of moesin on GEnCs and the binding of anti-MPO antibody to moesin.
The colocalization of moesin expression and anti-MPO antibody binding can be
detected. Little, if any, MPO was expressed in GEnCs. HMGB1 increased GEnC
activation and injury in the presence of patient-derived MPO-ANCA-positive IgGs
through moesin. The effects of HMGB1 on expression of moesin on GEnCs, anti-MPO
antibody binding to GEnCs, GEnC activation and injury were mainly toll like
receptor 4 (TLR4) dependent. CONCLUSIONS: HMGB1 can increase the expression of
moesin but not MPO on GEnCs, and can further participate in MPO-ANCA-induced GEnC
activation and injury by cross-reactivity between moesin and anti-MPO antibody.
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