Abstract
BackgroundAntimicrobial peptides are important components of the host defence with a broad range of functions including direct antimicrobial activity and modulation of inflammation. Lack of cathelin-related antimicrobial peptide (CRAMP) was associated with higher mortality and bacterial burden and impaired neutrophil granulocyte infiltration in a model of pneumococcal meningitis. The present study was designed to characterize the effects of CRAMP deficiency on glial response and phagocytosis after exposure to bacterial stimuli.MethodsCRAMP-knock out and wildtype glial cells were exposed to bacterial supernatants from Streptococcus pneumoniae and Neisseria meningitides or the bacterial cell wall components lipopolysaccharide and peptidoglycan. Cell viability, expression of pro- and anti-inflammatory mediators and activation of signal transduction pathways, phagocytosis rate and glial cell phenotype were investigated by means of cell viability assays, immunohistochemistry, real-time RT-PCR and Western blot.ResultsCRAMP-deficiency was associated with stronger expression of pro-inflammatory and weakened expression of anti-inflammatory cytokines indicating a higher degree of glial cell activation even under resting-state conditions. Furthermore, increased translocation of nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells was observed and phagocytosis of S. pneumoniae was reduced in CRAMP-deficient microglia indicating impaired antimicrobial activity.ConclusionsIn conclusion, the present study detected severe alterations of the glial immune response due to lack of CRAMP. The results indicate the importance of CRAMP to maintain and regulate the delicate balance between beneficial and harmful immune response in the brain.
Highlights
Antimicrobial peptides are important components of the host defence with a broad range of functions including direct antimicrobial activity and modulation of inflammation
Own investigations revealed an increase of Human cathelicidin (LL-37) and psoriasin in the cerebrospinal fluid (CSF) of patients suffering from bacterial meningitis [10, 11]
Own previous investigations revealed that lack of cathelin-related antimicrobial peptide (CRAMP) led to a higher mortality rate in bacterial meningitis; a phenomenon that was associated with increased bacterial burden and decreased neutrophil granulocyte infiltration of the meninges
Summary
Antimicrobial peptides are important components of the host defence with a broad range of functions including direct antimicrobial activity and modulation of inflammation. Lack of cathelin-related antimicrobial peptide (CRAMP) was associated with higher mortality and bacterial burden and impaired neutrophil granulocyte infiltration in a model of pneumococcal meningitis. Activation of the CNS’s innate immune system leads to secretion of antimicrobial peptides (AMP) which have both anti-infective and immunomodulatory properties [4]. There is only one cathelicidin called LL-37 that functions as a mediator between the innate and adaptive immune response It is stored in granules of neutrophil granulocytes and thought to have diverse functions such as inducing chemotaxis, neutralizing endotoxin and supporting wound healing [7]. Mice lacking CRAMP were more susceptible to pneumococcal infection of the CNS leading to higher bacterial burden both inside the brain (cerebellum) and outside the CNS (blood and spleen) accompanied by decreased neutrophil granulocyte infiltration and higher mortality [16]
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