Toll-Like Receptor Stimulation Enhances Phagocytosis and Intracellular Killing of Nonencapsulated and Encapsulated Streptococcus pneumoniae by Murine Microglia

Department of Geriatrics, Evang. Krankenhaus Göttingen-Weende, An der Lutter 24, D-37075 Göttingen, Germany.
Infection and immunity (Impact Factor: 3.73). 11/2009; 78(2):865-71. DOI: 10.1128/IAI.01110-09
Source: PubMed


Toll-like receptors (TLRs) are crucial pattern recognition receptors in innate immunity that are expressed in microglia, the
resident macrophages of the brain. TLR2, -4, and -9 are important in the responses against Streptococcus pneumoniae, the most common agent causing bacterial meningitis beyond the neonatal period. Murine microglial cultures were stimulated
with agonists for TLR1/2 (Pam3CSK4), TLR4 (lipopolysaccharide), and TLR9 (CpG oligodeoxynucleotide) for 24 h and then exposed to either the encapsulated D39
(serotype 2) or the nonencapsulated R6 strain of S. pneumoniae. After stimulation, the levels of interleukin-6 and CCL5 (RANTES [regulated upon activation normal T-cell expressed and secreted])
were increased, confirming microglial activation. The TLR1/2, -4, and -9 agonist-stimulated microglia ingested significantly
more bacteria than unstimulated cells (P < 0.05). The presence of cytochalasin D, an inhibitor of actin polymerizaton, blocked >90% of phagocytosis. Along with an
increased phagocytic activity, the intracellular bacterial killing was also increased in TLR-stimulated cells compared to
unstimulated cells. Together, our data suggest that microglial stimulation by these TLRs may increase the resistance of the
brain against pneumococcal infections.

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Available from: Sven Hammerschmidt
    • "Pneumococcal cell wall components, peptidoglycan and lipoteichoic acid, trigger the release of potent proinflammatory mediators by microglia (Hanisch and others 2001; Kochan and others 2012). In addition, microglia are of specific interest in PM due to their phagocytic properties: alongside surface TLR2 and TLR4 signaling, microglial phagocytosis of live pneumococci (Ribes and others 2010) also elicits proinflammatory responses, likely through TLR9 (Albiger and others 2007). The proinflammatory cytokine interferon-gamma (IFNg) is well studied in inflammation models (Schroder and others 2004; Schoenborn and Wilson 2007) and its signaling mechanisms have been reviewed by Schroder and others (2004). "

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    • "Since bacterial DNA, unlike eukaryotic DNA contains a high rate of unmethylated cytosine-guanine (CpG) motifs [29], recent attention has focused on this epitope, which is a ligand of Toll-like receptor (TLR)-9. Stimulation of microglial cells with CpG oligonucleotides increased phagocytosis of E. coli, Streptococcus pneumoniae and Cryptococcus neoformans and intracellular killing of these pathogens by microglial cells [30-32]. In various animal models, CpG ODN pre-treatment conferred protection against a variety of bloodstream and other extracerebral bacterial infections [33-35]. "
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    ABSTRACT: Background Palmitoylethanolamide (PEA), an endogenous lipid and a congener of anandamide, possesses a wide range of effects related to metabolic and cellular homeostasis including anti-inflammatory and neuroprotective properties. Methods In vitro, we studied the ability of macrophages to phagocytose Escherichia coli K1 after stimulation with increasing doses of PEA. In vivo, wild-type mice were treated with PEA intraperitoneally 12 hours and 30 minutes before infection. Meningoencephalitis or sepsis was induced by intracerebral or intraperitoneal infection with E. coli K1. Results Stimulation of macrophages with PEA for 30 minutes increased the phagocytosis of E. coli K1 without inducing the release of TNFα or CXCL1. Intracellular killing of E. coli K1 was higher in PEA-stimulated than in unstimulated peritoneal macrophages and microglial cells. Pre-treatment with PEA significantly increased survival of mice challenged intracerebrally or intraperitoneally with E. coli K1. This effect was associated with a decreased production of CXCL1, IL-1β and IL-6 in homogenates of spleen and cerebellum in mice treated with PEA. Conclusions Our observations suggest that these protective effects of PEA in mice can increase the resistance to bacterial infections without the hazard of collateral damage by excessive stimulation of phagocytes.
    Full-text · Article · Jun 2014 · Journal of Neuroinflammation
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    • "These agents also increased intracellular bacterial killing. The presence of a bacterial capsule as one important virulence factor decreased the rate of phagocytosis of E. coli and S. pneumoniae by one order of magnitude compared to unencapsulated strains (Ribes et al., 2009, 2010a,b, 2012). Agonists of the innate immune system also enhanced the phagocytosis of Cryptococcus neoformans (Redlich et al., 2013). "
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    ABSTRACT: In healthy individuals, infections of the central nervous system (CNS) are comparatively rare. Based on the ability of microglial cells to phagocytose and kill pathogens and on clinical findings in immunocompromised patients with CNS infections, we hypothesize that an intact microglial function is crucial to protect the brain from infections. Phagocytosis of pathogens by microglial cells can be stimulated by agonists of receptors of the innate immune system. Enhancing this pathway to increase the resistance of the brain to infections entails the risk of inducing collateral damage to the nervous tissue. The diversity of microglial cells opens avenue to selectively stimulate sub-populations responsible for the defence against pathogens without stimulating sub-populations which are responsible for collateral damage to the nervous tissue. Palmitoylethanolamide (PEA), an endogenous lipid, increased phagocytosis of bacteria by microglial cells in vitro without a measurable proinflammatory effect. It was tested clinically apparently without severe side effects. Glatiramer acetate increased phagocytosis of latex beads by microglia and monocytes, and dimethyl fumarate enhanced elimination of human immunodeficiency virus from infected macrophages without inducing a release of proinflammatory compounds. Therefore, the discovery of compounds which stimulate the elimination of pathogens without collateral damage of neuronal structures appears an achievable goal. PEA and, with limitations, glatiramer acetate and dimethyl fumarate appear promising candidates.
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