title: Role of purinergic signaling in experimental pneumococcal meningitis.
abstract: Excessive neutrophilic inflammation contributes to brain pathology and adverse outcome in pneumococcal meningitis (PM). Recently, we identified the NLRP3 inflammasome/interleukin (IL)-1β pathway as a key driver of inflammation in PM. A critical membrane receptor for NLRP3 inflammasome activation is the ATP-activated P2 purinoceptor (P2R) P2X7. Thus, we hypothesized involvement of ATP and P2Rs in PM. The functional role of ATP was investigated in a mouse meningitis model using P2R antagonists. Brain expression of P2Rs was assessed by RT-PCR. ATP levels were determined in murine CSF and cell culture experiments. Treatment with the P2R antagonists suramin or brilliant blue G did not have any impact on disease course. This lack of effect might be attributed to meningitis-associated down-regulation of brain P2R expression and/or a drop of cerebrospinal fluid (CSF) ATP, as demonstrated by RT-PCR and ATP analyses. Supplemental cell culture experiments suggest that the reduction in CSF ATP is, at least partly, due to ATP hydrolysis by ectonucleotidases of neutrophils and macrophages. In conclusion, this study suggests that ATP-P2R signaling is only of minor or even no significance in PM. This may be explained by down-regulation of P2R expression and decreased CSF ATP levels.
authors.affiliation: Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Zierhut
authors.affiliation: Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Dyckhoff
authors.affiliation: Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Ilias
authors.initials: I
authors.lastname: Masouris
authors.affiliation: Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Klein
authors.affiliation: Department Genetics of Microorganisms, Interfaculty Institute for Genetics and Functional Genomics, Ernst Moritz Arndt University Greifswald, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Hammerschmidt
authors.affiliation: Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Hans-Walter
authors.initials: HW
authors.lastname: Pfister
authors.affiliation: Department of Pneumology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: Korcan
authors.initials: K
authors.lastname: Ayata
authors.affiliation: Department of Pneumology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Idzko
authors.affiliation: Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Koedel
mesh_terms: D000255:Adenosine Triphosphate / Q000134:cerebrospinal fluid; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001081:Apyrase / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D018450:Disease Progression; D005110:Extracellular Space / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D008297:Male; D008586:Meningitis, Pneumococcal / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D058914:Purinergic Antagonists / Q000494:pharmacology; D011983:Receptors, Purinergic / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000502:physiology
chemical_list: D015703:Antigens, CD; D058914:Purinergic Antagonists; D011983:Receptors, Purinergic; D000255:Adenosine Triphosphate; D001081:Apyrase; C067869:CD39 antigen