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.
Highlights
Bacterial meningitis is among the worldwide top ten causes of mortality from infectious diseases, and many of the survivors show significant long-term neurologic disabilities[1]
Recent data from our group suggested an involvement of extracellular ATP (eATP) in NLRP3-inflammasome–dependent IL-1βrelease by differentiated human THP-1 cells upon exposure to S. pneumoniae[19]
Concentrations of IL-1βare elevated in cerebrospinal fluid (CSF) samples from patients with bacterial meningitis and correlate significantly with CSF leukocyte counts and clinical outcome[10]
Summary
Bacterial meningitis is among the worldwide top ten causes of mortality from infectious diseases, and many of the survivors show significant long-term neurologic disabilities[1]. Pneumococcal infection of the leptomeninges generates a powerful inflammatory reaction which contributes essentially to meningitis-associated brain damage[3,4,5]. Once in the extracellular space, ATP can behave as a “danger signal” and directly activate two families of plasma membrane receptors named P2 receptors (P2R), P2X and P2Y receptors[13,16] Members of both families of P2R have been implicated in the modulation of immune responses by a variety of mechanisms including regulation of neutrophil functions, such as adherence, chemotaxis, phagocytosis, and oxidative burst, as well as macrophage function, such as non-directed migration, phagocytic clearance of apoptotic cells, and cytokine release ( of IL-1β)[13,14,16]. This study aimed to assess the functional relevance of eATP in pneumococcal meningitis (PM) which represents a common and very serious form of brain infection
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