JinChao Hou1, QiXing Chen2, XiaoLiang Wu1, DongYan Zhao3, Hadas Reuveni4, Tamar Licht4, MengLong Xu1, Hu Hu5, Andreas Hoeft3, Shmuel A Ben-Sasson4, Qiang Shu2, XiangMing Fang1. 1. 1 Department of Anesthesiology and Intensive Care, The First Affiliated Hospital. 2. 2 The Children's Hospital, and. 3. 3 Department of Anesthesiology and Intensive Care Medicine, University of Bonn Medical Center, Bonn, Germany; and. 4. 4 Department of Developmental Biology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel. 5. 5 Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, China.
Abstract
RATIONALE: Efficient elimination of pathogenic bacteria is a critical determinant in the outcome of sepsis. Sphingosine-1-phosphate receptor 3 (S1PR3) mediates multiple aspects of the inflammatory response during sepsis, but whether S1PR3 signaling is necessary for eliminating the invading pathogens remains unknown. OBJECTIVES: To investigate the role of S1PR3 in antibacterial immunity during sepsis. METHODS: Loss- and gain-of-function experiments were performed using cell and murine models. S1PR3 levels were determined in patients with sepsis and healthy volunteers. MEASUREMENTS AND MAIN RESULTS: S1PR3 protein levels were up-regulated in macrophages upon bacterial stimulation. S1pr3-/- mice showed increased mortality and increased bacterial burden in multiple models of sepsis. The transfer of wild-type bone marrow-derived macrophages rescued S1pr3-/- mice from lethal sepsis. S1PR3-overexpressing macrophages further ameliorated the mortality rate of sepsis. Loss of S1PR3 led to markedly decreased bacterial killing in macrophages. Enhancing endogenous S1PR3 activity using a peptide agonist potentiated the macrophage bactericidal function and improved survival rates in multiple models of sepsis. Mechanically, the reactive oxygen species levels were decreased and phagosome maturation was delayed in S1pr3-/- macrophages due to impaired recruitment of vacuolar protein-sorting 34 to the phagosomes. In addition, S1RP3 expression levels were elevated in monocytes from patients with sepsis. Higher levels of monocytic S1PR3 were associated with efficient intracellular bactericidal activity, better immune status, and preferable outcomes. CONCLUSIONS: S1PR3 signaling drives bacterial killing and is essential for survival in bacterial sepsis. Interventions targeting S1PR3 signaling could have translational implications for manipulating the innate immune response to combat pathogens.
RATIONALE: Efficient elimination of pathogenic bacteria is a critical determinant in the outcome of sepsis. Sphingosine-1-phosphate receptor 3 (S1PR3) mediates multiple aspects of the inflammatory response during sepsis, but whether S1PR3 signaling is necessary for eliminating the invading pathogens remains unknown. OBJECTIVES: To investigate the role of S1PR3 in antibacterial immunity during sepsis. METHODS: Loss- and gain-of-function experiments were performed using cell and murine models. S1PR3 levels were determined in patients with sepsis and healthy volunteers. MEASUREMENTS AND MAIN RESULTS:S1PR3 protein levels were up-regulated in macrophages upon bacterial stimulation. S1pr3-/- mice showed increased mortality and increased bacterial burden in multiple models of sepsis. The transfer of wild-type bone marrow-derived macrophages rescued S1pr3-/- mice from lethal sepsis. S1PR3-overexpressing macrophages further ameliorated the mortality rate of sepsis. Loss of S1PR3 led to markedly decreased bacterial killing in macrophages. Enhancing endogenous S1PR3 activity using a peptide agonist potentiated the macrophage bactericidal function and improved survival rates in multiple models of sepsis. Mechanically, the reactive oxygen species levels were decreased and phagosome maturation was delayed in S1pr3-/- macrophages due to impaired recruitment of vacuolar protein-sorting 34 to the phagosomes. In addition, S1RP3 expression levels were elevated in monocytes from patients with sepsis. Higher levels of monocytic S1PR3 were associated with efficient intracellular bactericidal activity, better immune status, and preferable outcomes. CONCLUSIONS:S1PR3 signaling drives bacterial killing and is essential for survival in bacterial sepsis. Interventions targeting S1PR3 signaling could have translational implications for manipulating the innate immune response to combat pathogens.
Authors: Anna V Mikhaylova; Caitlin P McHugh; Linda M Polfus; Laura M Raffield; Meher Preethi Boorgula; Thomas W Blackwell; Jennifer A Brody; Jai Broome; Nathalie Chami; Ming-Huei Chen; Matthew P Conomos; Corey Cox; Joanne E Curran; Michelle Daya; Lynette Ekunwe; David C Glahn; Nancy Heard-Costa; Heather M Highland; Brian D Hobbs; Yann Ilboudo; Deepti Jain; Leslie A Lange; Tyne W Miller-Fleming; Nancy Min; Jee-Young Moon; Michael H Preuss; Jonathon Rosen; Kathleen Ryan; Albert V Smith; Quan Sun; Praveen Surendran; Paul S de Vries; Klaudia Walter; Zhe Wang; Marsha Wheeler; Lisa R Yanek; Xue Zhong; Goncalo R Abecasis; Laura Almasy; Kathleen C Barnes; Terri H Beaty; Lewis C Becker; John Blangero; Eric Boerwinkle; Adam S Butterworth; Sameer Chavan; Michael H Cho; Hélène Choquet; Adolfo Correa; Nancy Cox; Dawn L DeMeo; Nauder Faraday; Myriam Fornage; Robert E Gerszten; Lifang Hou; Andrew D Johnson; Eric Jorgenson; Robert Kaplan; Charles Kooperberg; Kousik Kundu; Cecelia A Laurie; Guillaume Lettre; Joshua P Lewis; Bingshan Li; Yun Li; Donald M Lloyd-Jones; Ruth J F Loos; Ani Manichaikul; Deborah A Meyers; Braxton D Mitchell; Alanna C Morrison; Debby Ngo; Deborah A Nickerson; Suraj Nongmaithem; Kari E North; Jeffrey R O'Connell; Victor E Ortega; Nathan Pankratz; James A Perry; Bruce M Psaty; Stephen S Rich; Nicole Soranzo; Jerome I Rotter; Edwin K Silverman; Nicholas L Smith; Hua Tang; Russell P Tracy; Timothy A Thornton; Ramachandran S Vasan; Joe Zein; Rasika A Mathias; Alexander P Reiner; Paul L Auer Journal: Am J Hum Genet Date: 2021-09-27 Impact factor: 11.043
Authors: Cynthia Weigel; Sören S Hüttner; Kristin Ludwig; Nadine Krieg; Susann Hofmann; Nathalie H Schröder; Linda Robbe; Stefan Kluge; Axel Nierhaus; Martin S Winkler; Ignacio Rubio; Julia von Maltzahn; Sarah Spiegel; Markus H Gräler Journal: EBioMedicine Date: 2020-07-22 Impact factor: 8.143