Open AccessApolipoprotein Mimetic Peptide Inhibits Neutrophil-Driven Inflammatory Damage via Membrane Remodeling and Suppression of Cell Lysis
Author(s) -
Michelle W. Lee,
Elizabeth Wei-Chia Luo,
Carlos Silvestre-Roig,
Yashes Srinivasan,
Kiyotaka Akabori,
Patricia Lemnitzer,
Nathan W. Schmidt,
Ghee Hwee Lai,
Christian Santangelo,
Oliver Soehnlein,
Gerard C. L. Wong
Publication year - 2021
Publication title -
acs nano
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.554
H-Index - 382
eISSN - 1936-086X
pISSN - 1936-0851
DOI - 10.1021/acsnano.1c03978
Subject(s) - microbiology and biotechnology , lytic cycle , histone , biology , membrane curvature , extracellular , programmed cell death , intracellular , cell membrane , inflammation , lysis , neutrophil extracellular traps , cell , membrane , chemistry , biophysics , biochemistry , immunology , lipid bilayer , apoptosis , virus , gene
Neutrophils are crucial for host defense but are notorious for causing sterile inflammatory damage. Activated neutrophils in inflamed tissue can liberate histone H4, which was recently shown to perpetuate inflammation by permeating membranes via the generation of negative Gaussian curvature (NGC), leading to lytic cell death. Here, we show that it is possible to build peptides or proteins that cancel NGC in membranes and thereby suppress pore formation, and demonstrate that they can inhibit H4 membrane remodeling and thereby reduce histone H4-driven lytic cell death and resultant inflammation. As a demonstration of principle, we use apolipoprotein A-I (apoA-I) mimetic peptide apoMP 1 . X-ray structural studies and theoretical calculations show that apoMP 1 induces nanoscopic positive Gaussian curvature (PGC), which interacts with the NGC induced by the N-terminus of histone H4 (H4n) to inhibit membrane permeation. Interestingly, we show that induction of PGC can inhibit membrane-permeating activity in general and "turn off" diverse membrane-permeating molecules besides H4n. In vitro experiments show an apoMP 1 dose-dependent rescue of H4 cytotoxicity. Using a mouse model, we show that tissue accumulation of neutrophils, release of neutrophil extracellular traps (NETs), and extracellular H4 all strongly correlate independently with local tissue cell death in multiple organs, but administration of apoMP 1 inhibits histone H4-mediated cytotoxicity and strongly prevents organ tissue damage.