PAD4-deficiency does not affect bacteremia in polymicrobial sepsis and ameliorates endotoxemic shock

TY - JOUR

T1 - PAD4-deficiency does not affect bacteremia in polymicrobial sepsis and ameliorates endotoxemic shock

AU - Martinod, Kimberly

AU - Fuchs, Tobias A

AU - Zitomersky, Naamah L

AU - Wong, Siu Ling

AU - Demers, Melanie

AU - Gallant, Maureen

AU - Wang, Yanming

AU - Wagner, Denisa D

N1 - © 2015 by The American Society of Hematology.

PY - 2015/3/19

Y1 - 2015/3/19

N2 - Neutrophil extracellular traps (NETs), consisting of nuclear DNA with histones and microbicidal proteins, are expelled from activated neutrophils during sepsis. NETs were shown to trap microbes, but they also fuel cardiovascular, thrombotic, and autoimmune disease. The role of NETs in sepsis, particularly the balance between their antimicrobial and cytotoxic actions, remains unclear. Neutrophils from peptidylarginine deiminase 4-(PAD4(-/-)) deficient mice, which lack the enzyme allowing for chromatin decondensation and NET formation, were evaluated. We found that neutrophil functions involved in bacterial killing, other than NETosis, remained intact. Therefore, we hypothesized that prevention of NET formation might not have devastating consequences in sepsis. To test this, we subjected the PAD4(-/-) mice to mild and severe polymicrobial sepsis produced by cecal ligation and puncture. Surprisingly, under septic conditions, PAD4(-/-) mice did not fare worse than wild-type mice and had comparable survival. In the presence of antibiotics, PAD4-deficiency resulted in slightly accelerated mortality but bacteremia was unaffected. PAD4(-/-) mice were partially protected from lipopolysaccharide-induced shock, suggesting that PAD4/NETs may contribute to the toxic inflammatory and procoagulant host response to endotoxin. We propose that preventing NET formation by PAD4 inhibition in inflammatory or thrombotic diseases is not likely to increase host vulnerability to bacterial infections.

AB - Neutrophil extracellular traps (NETs), consisting of nuclear DNA with histones and microbicidal proteins, are expelled from activated neutrophils during sepsis. NETs were shown to trap microbes, but they also fuel cardiovascular, thrombotic, and autoimmune disease. The role of NETs in sepsis, particularly the balance between their antimicrobial and cytotoxic actions, remains unclear. Neutrophils from peptidylarginine deiminase 4-(PAD4(-/-)) deficient mice, which lack the enzyme allowing for chromatin decondensation and NET formation, were evaluated. We found that neutrophil functions involved in bacterial killing, other than NETosis, remained intact. Therefore, we hypothesized that prevention of NET formation might not have devastating consequences in sepsis. To test this, we subjected the PAD4(-/-) mice to mild and severe polymicrobial sepsis produced by cecal ligation and puncture. Surprisingly, under septic conditions, PAD4(-/-) mice did not fare worse than wild-type mice and had comparable survival. In the presence of antibiotics, PAD4-deficiency resulted in slightly accelerated mortality but bacteremia was unaffected. PAD4(-/-) mice were partially protected from lipopolysaccharide-induced shock, suggesting that PAD4/NETs may contribute to the toxic inflammatory and procoagulant host response to endotoxin. We propose that preventing NET formation by PAD4 inhibition in inflammatory or thrombotic diseases is not likely to increase host vulnerability to bacterial infections.

KW - Animals

KW - Anti-Bacterial Agents

KW - Bacteremia

KW - Crosses, Genetic

KW - Endotoxemia

KW - Flow Cytometry

KW - Histones

KW - Hydrolases

KW - Inflammation

KW - Lipopolysaccharides

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Neutrophil Activation

KW - Neutrophils

KW - Peritonitis

KW - Sepsis

U2 - 10.1182/blood-2014-07-587709

DO - 10.1182/blood-2014-07-587709

M3 - SCORING: Journal article

C2 - 25624317

VL - 125

SP - 1948

EP - 1956

JO - BLOOD

JF - BLOOD

SN - 0006-4971

IS - 12

ER -