Abstract
Sepsis claims an estimated 30 million episodes and 6 million deaths per year, and treatment options are rather limited. Human neutrophil peptides 1-3 (HNP1-3) are the most abundant neutrophil granule proteins but their neutrophil content varies because of unusually extensive gene copy number polymorphism. A genetic association study found that increased copy number of the HNP-encoding gene DEFA1/DEFA3 is a risk factor for organ dysfunction during sepsis development. However, direct experimental evidence demonstrating that these risk alleles are pathogenic for sepsis is lacking because the genes are present only in some primates and humans. Here, we generate DEFA1/DEFA3 transgenic mice with neutrophil-specific expression of the peptides. We show that mice with high copy number of DEFA1/DEFA3 genes have more severe sepsis-related vital organ damage and mortality than mice with low copy number of DEFA1/DEFA3 or wild-type mice, resulting from more severe endothelial barrier dysfunction and endothelial cell pyroptosis after sepsis challenge. Mechanistically, HNP-1 induces endothelial cell pyroptosis via P2X7 receptor-mediating canonical caspase-1 activation in a NLRP3 inflammasome-dependent manner. Based on these findings, we engineered a monoclonal antibody against HNP-1 to block the interaction with P2X7 and found that the blocking antibody protected mice carrying high copy number of DEFA1/DEFA3 from lethal sepsis. We thus demonstrate that DEFA1/DEFA3 copy number variation strongly modulates sepsis development in vivo and explore a paradigm for the precision treatment of sepsis tailored by individual genetic information.
Highlights
Sepsis claims an estimated 30 million episodes and 6 million deaths per year, and treatment options are rather limited
This amino acid is missing in human neutrophil peptides (HNPs)-2 peptide, and HNP-2 is thought to be a proteolytic product of HNP-1 and HNP-3 [16, 17]
We show that transgenic mice with high copy number of DEFA1/ DEFA3 [encoding human neutrophil peptides 1–3 (HNP1–3)] suffer from more severe sepsis because of more extensive endothelial barrier dysfunction and endothelial cell pyroptosis
Summary
Sepsis claims an estimated 30 million episodes and 6 million deaths per year, and treatment options are rather limited. A genetic association study found that increased copy number of the HNP-encoding gene DEFA1/DEFA3 is a risk factor for organ dysfunction during sepsis development. HNP-1 induces endothelial cell pyroptosis via P2X7 receptor-mediating canonical caspase-1 activation in a NLRP3 inflammasome-dependent manner Based on these findings, we engineered a monoclonal antibody against HNP-1 to block the interaction with P2X7 and found that the blocking antibody protected mice carrying high copy number of DEFA1/DEFA3 from lethal sepsis. This amino acid is missing in HNP-2 peptide, and HNP-2 is thought to be a proteolytic product of HNP-1 and HNP-3 [16, 17] In addition to their broad repertoire of antimicrobial activities [18, 19], HNP1–3 exert multiple immunomodulatory effects [20,21,22], as well as early release alarmin activity to initiate the host response upon microbial invasion or tissue injury/damage [23]. Our previous genetic association study found that the doses of genes encoding
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