Highlights • A single LPS stimulus results in a prolonged blunted microglia immune response. • Tolerant microglia are epigenetically silenced in vitro and in vivo. • NF-κB subunit RelB is required ...for epigenetic silencing of microglia. • Tolerant microglia display increased phagocytic activity.
Microglial Phenotype and Adaptation Eggen, B. J. L.; Raj, D.; Hanisch, U.-K. ...
Journal of neuroimmune pharmacology,
09/2013, Letnik:
8, Številka:
4
Journal Article
Recenzirano
Microglia are the prime innate immune cells of the central nervous system. They can transit from a (so-called) resting state under homeostatic conditions towards a pro-inflammatory activation state ...upon homeostatic disturbances. Under neurodegenerative conditions, microglia have been largely perceived as neurotoxic cells. It is now becoming clear that resting microglia are not inactive but that they serve house-keeping functions. Moreover, microglia activity is not limited to proinflammatory responses, but covers a spectrum of reactive profiles. Depending on the actual situation, activated microglia display specific effector functions supporting inflammation, tissue remodeling, synaptic plasticity and neurogenesis. Many of these functions not only relate to the current state of the local neural environment but also depend on previous experience. In this review, we address microglia functions with respect to determining factors, phenotypic presentations, adaptation to environmental signals and aging. Finally, we point out primary mechanisms of microglia activation, which may comprise therapeutic targets to control neuro-inflammatory and neurodegenerative activity.
Mutations and activation of the PI3K signaling pathway in breast cancer cells have been linked to brain metastases. However, here we describe that in some breast cancer brain metastases samples the ...protein expression of PI3K signaling components is restricted to the metastatic microenvironment. In contrast to the therapeutic effects of PI3K inhibition on the breast cancer cells, the reaction of the brain microenvironment is less understood. Therefore we aimed to quantify the PI3K pathway activity in breast cancer brain metastasis and investigate the effects of PI3K inhibition on the central nervous system (CNS) microenvironment. First, to systematically quantify the PI3K pathway activity in breast cancer brain metastases, we performed a prospective biomarker study using a reverse phase protein array (RPPA). The majority, namely 30 out of 48 (62.5%) brain metastatic tissues examined, revealed high PI3K signaling activity that was associated with a median overall survival (OS) of 9.41 months, while that of patients, whose brain metastases showed only moderate or low PI3K activity, amounted to only 1.93 and 6.71 months, respectively. Second, we identified PI3K as a master regulator of metastasis‐promoting macrophages/microglia during CNS colonization; and treatment with buparlisib (BKM120), a pan‐PI3K Class I inhibitor with a good blood‐brain‐barrier penetrance, reduced their metastasis‐promoting features. In conclusion, PI3K signaling is active in the majority of breast cancer brain metastases. Since PI3K inhibition does not only affect the metastatic cells but also re‐educates the metastasis‐promoting macrophages/microglia, PI3K inhibition may hold considerable promise in the treatment of brain metastasis and the respective microenvironment.
Main Points
Blockade of PI3K signaling in macrophages/microglia in brain metastasis models leads to (a) a more metastasis‐suppressing macrophage phenotype, (b) changes in the astrogliosis, and (c) reduced tumor cell infiltration into the brain parenchyma.
Bacterial meningitis is a fatal disease with a mortality up to 30% and neurological sequelae in one fourth of survivors. Available vaccines do not fully protect against this lethal disease. Here, we ...report the protective effect of synthetic oligodeoxynucleotides containing unmethylated cytosine-guanine motifs (CpG ODN) against the most frequent form of bacterial meningitis caused by Streptococcus pneumoniae.
Three days prior to the induction of meningitis by intracerebral injection of S. pneumoniae D39, wild-type and Toll-like receptor (TLR9)
mice received an intraperitoneal injection of 100 μg CpG ODN or vehicle. To render mice neutropenic, anti-Ly-6G monoclonal antibody was daily administrated starting 4 days before infection with a total of 7 injections. Kaplan-Meier survival analyses and bacteriological studies, in which mice were sacrificed 24 h and 36 h after infection, were performed.
Pre-treatment with 100 μg CpG ODN prolonged survival of immunocompetent and neutropenic wild-type mice but not of TLR9
mice. There was a trend towards lower mortality in CpG ODN-treated immunocompetent and neutropenic wild-type mice. CpG ODN caused an increase of IL-12/IL-23p40 levels in the spleen and serum in uninfected animals. The effects of CpG ODN on bacterial concentrations and development of clinical symptoms were associated with an increased number of microglia in the CNS during the early phase of infection. Elevated concentrations of IL-12/IL-23p40 and MIP-1α correlated with lower bacterial concentrations in the blood and spleen during infection.
Pre-conditioning with CpG ODN strengthened the resistance of neutropenic and immunocompetent mice against S. pneumoniae meningitis in the presence of TLR9. Administration of CpG ODN decreased bacterial burden in the cerebellum and reduced the degree of bacteremia. Systemic administration of CpG ODN may help to prevent or slow the progression to sepsis of bacterial CNS infections in healthy and immunocompromised individuals even after direct inoculation of bacteria into the intracranial compartments, which can occur after sinusitis, mastoiditis, open head trauma, and surgery, including placement of an external ventricular drain.
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