Sung Kyun Lee,1 Sang Doo Kim,1 Minsoo Kook,1 Ha Young Lee,1,2 Jaewang Ghim,3 Youngwoo Choi,3 Brian A. Zabel,4 Sung Ho Ryu,3 and Yoe-Sik Bae1,2,5,*
1Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Republic of Korea
2Mitochondria Hub Regulation Center, Dong-A University, Busan 49201, Republic of Korea
3Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, Republic of Korea
4Palo Alto Veterans Institute for Research, Veterans Affairs Hospital, Palo Alto, CA 94304
5Department of Health Sciences and Technology, Samsung Advanced Institute for Heallth Sciences and Technology, Sungkyunkwan University, Seoul 06351, Republic of Korea
*CORRESPONDENCE : Yoe-Sik Bae
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.