Phospholipase D2 drives mortality in sepsis by inhibiting neutrophil extracellular trap formation and down-regulating CXCR2.
We determined the function of phospholipase D2 (PLD2) in host defense in highly lethal mouse models of sepsis using PLD2(-/-) mice and a PLD2-specific inhibitor. PLD2 deficiency not only increases survival but also decreases vital organ damage during experimental sepsis. Production of several inflammatory cytokines (TNF, IL-1β, IL-17, and IL-23) and the chemokine CXCL1, as well as cellular apoptosis in immune tissues, kidney, and liver, are markedly decreased in PLD2(-/-) mice. Bactericidal activity is significantly increased in PLD2(-/-) mice, which is mediated by increased neutrophil extracellular trap formation and citrullination of histone 3 through peptidylarginine deiminase activation. Recruitment of neutrophils to the lung is markedly increased in PLD2(-/-) mice. Furthermore, LPS-induced induction of G protein-coupled receptor kinase 2 (GRK2) and down-regulation of CXCR2 are markedly attenuated in PLD2(-/-) mice. A CXCR2-selective antagonist abolishes the protection conferred by PLD2 deficiency during experimental sepsis, suggesting that enhanced CXCR2 expression, likely driven by GRK2 down-regulation in neutrophils, promotes survival in PLD2(-/-) mice. Furthermore, adoptively transferred PLD2(-/-) neutrophils significantly protect WT recipients against sepsis-induced death compared with transferred WT neutrophils. We suggest that PLD2 in neutrophils is essential for the pathogenesis of experimental sepsis and that pharmaceutical agents that target PLD2 may prove beneficial for septic patients.
Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Republic of Korea.
Sung Kyun
SK
Lee
Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Republic of Korea.
Sang Doo
SD
Kim
Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Republic of Korea.
Minsoo
M
Kook
Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Republic of Korea Mitochondria Hub Regulation Center, Dong-A University, Busan 49201, Republic of Korea.
Ha Young
HY
Lee
Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, Republic of Korea.
Jaewang
J
Ghim
Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, Republic of Korea.
Youngwoo
Y
Choi
Palo Alto Veterans Institute for Research, Veterans Affairs Hospital, Palo Alto, CA 94304.
Brian A
BA
Zabel
Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, Republic of Korea.
Sung Ho
SH
Ryu
Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Republic of Korea Mitochondria Hub Regulation Center, Dong-A University, Busan 49201, Republic of Korea Department of Health Sciences and Technology, Samsung Advanced Institute for Heallth Sciences and Technology, Sungkyunkwan University, Seoul 06351, Republic of Korea yoesik@skku.edu.
Yoe-Sik
YS
Bae
D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D065206:Extracellular Traps / Q000235:genetics / Q000378:metabolism*; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000235:genetics; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D010739:Phospholipase D / Q000235:genetics / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000096:biosynthesis* / Q000235:genetics; D018805:Sepsis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D016207:Cytokines; D008070:Lipopolysaccharides; D023063:Receptors, Interleukin-8B; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2; C105606:phospholipase D2; D010739:Phospholipase D