title: Hyperresponsiveness of mice deficient in plasma-secreted sphingomyelinase reveals its pivotal role in early phase of host response.
abstract: Plasma secretion of acid sphingomyelinase is a hallmark of cellular stress response resulting in the formation of membrane embedded ceramide-enriched lipid rafts and the reorganization of receptor complexes. Consistently, decompartmentalization of ceramide formation from inert sphingomyelin has been associated with signaling events and regulation of the cellular phenotype. Herein, we addressed the question of whether the secretion of acid sphingomyelinase is involved in host response during sepsis. We found an exaggerated clinical course in mice genetically deficient in acid sphingomyelinase characterized by an increased bacterial burden, an increased phagocytotic activity, and a more pronounced cytokine storm. Moreover, on a functional level, leukocyte-endothelial interaction was found diminished in sphingomyelinase-deficient animals corresponding to a distinct leukocytes' phenotype with respect to rolling and sticking as well as expression of cellular surface proteins. We conclude that hydrolysis of membrane-embedded sphingomyelin, triggered by circulating sphingomyelinase, plays a pivotal role in the first line of defense against invading microorganisms. This function might be essential during the early phase of infection leading to an adaptive response of remote cells and tissues.
authors.affiliation: Center of Sepsis Control and Care, Jena University Hospital, Jena, Germany.
authors.forename: Nayla
authors.initials: N
authors.lastname: Jbeily
authors.forename: Iris
authors.initials: I
authors.lastname: Suckert
authors.forename: Falk A
authors.initials: FA
authors.lastname: Gonnert
authors.forename: Benedikt
authors.initials: B
authors.lastname: Acht
authors.forename: Clemens L
authors.initials: CL
authors.lastname: Bockmeyer
authors.forename: Sascha D
authors.initials: SD
authors.lastname: Grossmann
authors.forename: Markus F
authors.initials: MF
authors.lastname: Blaess
authors.forename: Anja
authors.initials: A
authors.lastname: Lueth
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Deigner
authors.forename: Michael
authors.initials: M
authors.lastname: Bauer
authors.forename: Ralf A
authors.initials: RA
authors.lastname: Claus
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D055786:Gene Knockout Techniques; D007962:Leukocytes / Q000276:immunology; D051379:Mice; D010976:Platelet Count; D018805:Sepsis / Q000097:blood / Q000201:enzymology* / Q000276:immunology*; D013108:Sphingomyelin Phosphodiesterase / Q000097:blood / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: D016207:Cytokines; D013108:Sphingomyelin Phosphodiesterase