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2018 ; 9
(ä): 558
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Inhibition of Immune Complex Complement Activation and Neutrophil Extracellular
Trap Formation by Peptide Inhibitor of Complement C1
#MMPMID29632531
Hair PS
; Enos AI
; Krishna NK
; Cunnion KM
Front Immunol
2018[]; 9
(ä): 558
PMID29632531
show ga
Two major aspects of systemic lupus erythematosus (SLE) pathogenesis that have
yet to be targeted therapeutically are immune complex-initiated complement
activation and neutrophil extracellular trap (NET) formation by neutrophils.
Here, we report in vitro testing of peptide inhibitor of complement C1 (PIC1) in
assays of immune complex-mediated complement activation in human sera and assays
for NET formation by human neutrophils. The lead PIC1 derivative, PA-dPEG24, was
able to dose-dependently inhibit complement activation initiated by multiple
types of immune complexes (IC), including C1-anti-C1q IC, limiting the generation
of pro-inflammatory complement effectors, including C5a and membrane attack
complex (sC5b-9). In several instances, PA-dPEG24 achieved complete inhibition
with complement effector levels equivalent to background. PA-dPEG24 was also able
to dose-dependently inhibit NET formation by human neutrophils stimulated by PMA,
MPO, or immune complex activated human sera. In several instances PA-dPEG24
achieved complete inhibition with NETosis with quantitation equivalent to
background levels. These results suggest that PA-dPEG24 inhibition of NETs occurs
by blocking the MPO pathway of NET formation. Together these results demonstrate
that PA-dPEG24 can inhibit immune complex activation of the complement system and
NET formation. This provides proof of concept that peptides can potentially be
developed to inhibit these two important contributors to rheumatologic pathology
that are currently untargeted by available therapies.