title: Chemokine Receptors, CXCR1 and CXCR2, Differentially Regulate Exosome Release in Hepatocytes.
abstract: Exosomes are small membrane vesicles released by different cell types, including hepatocytes, that play important roles in intercellular communication. We have previously demonstrated that hepatocyte-derived exosomes contain the synthetic machinery to form sphingosine-1-phosphate (S1P) in target hepatocytes resulting in proliferation and liver regeneration after ischemia/reperfusion (I/R) injury. We also demonstrated that the chemokine receptors, CXCR1 and CXCR2, regulate liver recovery and regeneration after I/R injury. In the current study, we sought to determine if the regulatory effects of CXCR1 and CXCR2 on liver recovery and regeneration might occur via altered release of hepatocyte exosomes. We found that hepatocyte release of exosomes was dependent upon CXCR1 and CXCR2. CXCR1-deficient hepatocytes produced fewer exosomes, whereas CXCR2-deficient hepatocytes produced more exosomes compared to their wild-type controls. In CXCR2-deficient hepatocytes, there was increased activity of neutral sphingomyelinase (Nsm) and intracellular ceramide. CXCR1-deficient hepatocytes had no alterations in Nsm activity or ceramide production. Interestingly, exosomes from CXCR1-deficient hepatocytes had no effect on hepatocyte proliferation, due to a lack of neutral ceramidase and sphingosine kinase. The data demonstrate that CXCR1 and CXCR2 regulate hepatocyte exosome release. The mechanism utilized by CXCR1 remains elusive, but CXCR2 appears to modulate Nsm activity and resultant production of ceramide to control exosome release. CXCR1 is required for packaging of enzymes into exosomes that mediate their hepatocyte proliferative effect.
authors.affiliation: Department of Surgery, University of Cincinnati, College of Medicine, Cincinnati, Ohio, United States of America.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nojima
authors.affiliation: Department of Surgery, University of Cincinnati, College of Medicine, Cincinnati, Ohio, United States of America.
authors.forename: Takanori
authors.initials: T
authors.lastname: Konishi
authors.affiliation: Department of Surgery, University of Cincinnati, College of Medicine, Cincinnati, Ohio, United States of America.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Freeman
authors.affiliation: Department of Surgery, University of Cincinnati, College of Medicine, Cincinnati, Ohio, United States of America.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Schuster
authors.affiliation: Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Japtok
authors.affiliation: Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kleuser
authors.affiliation: Department of Surgery, University of Cincinnati, College of Medicine, Cincinnati, Ohio, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Edwards
authors.affiliation: Department of Surgery, University of Cincinnati, College of Medicine, Cincinnati, Ohio, United States of America.|Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
authors.affiliation: Department of Surgery, University of Cincinnati, College of Medicine, Cincinnati, Ohio, United States of America.
authors.forename: Alex B
authors.initials: AB
authors.lastname: Lentsch
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D055572:Ceramidases / Q000378:metabolism; D055354:Exosomes / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D008246:Lysophospholipids / Q000096:biosynthesis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D023062:Receptors, Interleukin-8A / Q000235:genetics / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000075745:rab27 GTP-Binding Proteins; D000099157:Sphingosine Kinase
chemical_list: D055572:Ceramidases; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D013108:Sphingomyelin Phosphodiesterase; D013110:Sphingosine; D020691:rab GTP-Binding Proteins; D000075745:rab27 GTP-Binding Proteins; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C512958:Rab27b protein, mouse; C512962:Rab27a protein, mouse