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: Marco Zierhut, Susanne Dyckhoff, Ilias Masouris, Matthias Klein, Sven Hammerschmidt, Hans-Walter Pfister, Korcan Ayata, Marco Idzko, Uwe Koedel
• Journal: Scientific reports (Sci Rep) Vol. 7 Pg. 44625 (03 16 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28300164 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• Purinergic Antagonists
• Receptors, Purinergic
• Adenosine Triphosphate
• Apyrase
• CD39 antigen

Topics

• Adenosine Triphosphate (cerebrospinal fluid)
• Animals
• Antigens, CD (metabolism)
• Apyrase (metabolism)
• Bone Marrow Cells (drug effects, metabolism)
• Brain (metabolism)
• Disease Progression
• Extracellular Space (metabolism)
• Macrophage Activation (drug effects)
• Male
• Meningitis, Pneumococcal (cerebrospinal fluid, metabolism, microbiology, pathology)
• Mice, Inbred C57BL
• Neutrophils (drug effects, metabolism)
• Purinergic Antagonists (pharmacology)
• Receptors, Purinergic (metabolism)
• Signal Transduction (drug effects)
• Streptococcus pneumoniae (drug effects, physiology)