Apolipoprotein Mimetic Peptide Inhibits Neutrophil-Driven Inflammatory Damage via Membrane Remodeling and Suppression of Cell Lysis

Michelle W. Lee, Elizabeth Wei Chia Luo, Carlos Silvestre-Roig, Yashes Srinivasan, Kiyotaka Akabori, Patricia Lemnitzer, Nathan W. Schmidt, Ghee Hwee Lai, Christian D. Santangelo, Oliver Soehnlein, Gerard C.L. Wong

Research output: Contribution to journalArticlepeer-review

Abstract

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 apoMP1. X-ray structural studies and theoretical calculations show that apoMP1 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 apoMP1 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 apoMP1 inhibits histone H4-mediated cytotoxicity and strongly prevents organ tissue damage.

Original languageEnglish (US)
Pages (from-to)15930-15939
Number of pages10
JournalACS nano
Volume15
Issue number10
DOIs
StatePublished - Oct 26 2021

Keywords

  • apolipoprotein
  • cell death
  • chronic inflammation
  • membrane remodeling
  • neutrophils
  • peptide-membrane interactions

ASJC Scopus subject areas

  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)

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