Microglia-derived microvesicles affect microglia phenotype in glioma

Extracellular-released vesicles (EVs), such as microvesicles (MV) and exosomes (Exo) provide a new type of inter-cellular communication, directly transferring a ready to use box of information, consisting of proteins, lipids and nucleic acids. In the nervous system, EVs participate to neuron-glial cross-talk, a bidirectional communication important to preserve brain homeostasis and, when dysfunctional, involved in several CNS diseases. We investigated whether microglia-derived EVs could be used to transfer a protective phenotype to dysfunctional microglia in the context of a brain tumor. When MV, isolated from microglia stimulated with LPS/IFNg were brain injected in glioma-bearing mice, we observed a phenotype switch of tumor associated myeloid cells (TAMs) and a reduction of tumor size. Our findings indicate that the MV cargo, which contains upregulated transcripts for several inflammation-related genes, can transfer information in the brain of glioma bearing mice modifying microglial gene expression, reducing neuronal death and glioma invasion, thus promoting the recovery of brain homeostasis

CXCL16/CXCR6 axis drives microglia/macrophages phenotype in physiological conditions and plays a crucial role in glioma

Microglia are patrolling cells that sense changes in the brain microenvironment and respond acquiring distinct phenotypes that can be either beneficial or detrimental for brain homeostasis. Anti-inflammatory microglia release soluble factors that might promote brain repair; however, in glioma, anti-inflammatory microglia dampen immune response and promote a brain microenvironment that foster tumor growth and invasion. The chemokine CXCL16 is expressed in the brain, where it is neuroprotective against brain ischemia, and it has been found to be over-expressed in glioblastoma (GBM). Considering that CXCL16 specific receptor CXCR6 is diffusely expressed in the brain including in microglia cells, we wanted to investigate the role of CXCL16 in the modulation of microglia cell activity and phenotype, and in the progression of glioma. Here we report that CXCL16 drives microglia polarization toward an anti-inflammatory phenotype, also restraining microglia polarization toward an inflammatory phenotype upon LPS and IFN? stimulation. In the context of glioma, we demonstrate that CXCL16 released by tumor cells is determinant in promoting glioma associated microglia/macrophages (GAMs) modulation toward an anti-inflammatory/pro-tumor phenotype, and that cxcr6ko mice, orthotopically implanted into the brain with GL261 glioma cells,survive longer compared to wild-type mice. We also describe that CXCL16/CXCR6 signaling acts directly on mouse glioma cells, as well as human primary GBM cells, promoting tumor cell growth, migration and invasion. All together these data suggest that CXCL16 signaling could represent a good target to modulate microglia phenotype in order to restrain inflammation or to limit glioma progression

The chemokine CXCL16 modulates neurotransmitter release in hippocampal CA1 area.

Chemokines have several physio-pathological roles in the brain. Among them, the modulation of synaptic contacts and neurotransmission recently emerged as crucial activities during brain development, in adulthood, upon neuroinflammation and neurodegenerative diseases. CXCL16 is a chemokine normally expressed in the brain, where it exerts neuroprotective activity against glutamate-induced damages through cross communication with astrocytes and the involvement of the adenosine receptor type 3 (A3R) and the chemokine CCL2. Here we demonstrated for the first time that CXCL16 exerts a modulatory activity on inhibitory and excitatory synaptic transmission in CA1 area. We found that CXCL16 increases the frequency of the miniature inhibitory synaptic currents (mIPSCs) and the paired-pulse ratio (PPR) of evoked IPSCs(eIPSCs), suggesting a presynaptic modulation of the probability of GABA release. In addition, CXCL16 increases the frequency of the miniature excitatory synaptic currents (mEPSCs) and reduces the PPR of evoked excitatory transmission, indicating that the chemokine also modulates and enhances the release of glutamate. These effects were not present in the A3RKO mice and in WT slices treated with minocycline, confirming the involvement of A3 receptors and introducing microglial cells as key mediators of the modulatory activity of CXCL16 on neurons

A VST and VISTA study of globular clusters in NGC253

Aims. We analyze the properties of the sources in the NGC253 to define an up to date catalog of GC candidates in the galaxy. Methods. Our analysis is based on the science verification data of two ESO survey telescopes, VST and VISTA. Using ugri photometry from VST and JKs from VISTA, GC candidates were selected using the morpho-photometric and color properties of spectroscopically confirmed GCs available in the literature. The strength of the results was verified against available archival HST/ACS data from the GHOSTS survey. Results. The adopted GC selection leads to the definition of a sample of ~350 GC candidates. At visual inspection, we find that 82 objects match all the requirements for selecting GC candidates and 155 are flagged as uncertain GC candidate; 110 are unlikely GCs, most likely background galaxies. Furthermore, our analysis shows that four of the previously spectroscopically confirmed GCs, i.e., ~20% of the total spectroscopic sample, are more likely either background galaxies or high-velocity Milky Way stars. The radial density profile of the selected best candidates shows the typically observed r1/4-law radial profile. The analysis of the color distributions reveals only marginal evidence of the presence of color bimodality, which is normally observed in galaxies of similar luminosity. The GC luminosity function does not show the typical symmetry, mainly because of the lack of bright GCs. Part of the bright GCs missing might be at very large galactocentric distances or along the line of sight of the galaxy dusty disk. Conclusions. Using ugriJKs photometry we purged the list of GCs with spectroscopic membership and photometric GC candidates in NGC 253. Our results show that the use of either spectroscopic or photometric data only does not generally ensure a contaminant-free sample and a combination of both spectroscopy and photometry is preferred.Comment: 24 pages, 15 figures, Accepted by Astronomy and Astrophysic

Inflammation, neurodegeneration and protein aggregation in the retina as ocular biomarkers for Alzheimer’s Disease in the 3xTg-AD mouse model

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. In the pathogenesis of AD a pivotal role is played by two neurotoxic proteins that aggregate and accumulate in the central nervous system: amyloid beta and hyper-phosphorylated tau. Accumulation of extracellular amyloid beta plaques and intracellular hyper-phosphorylated tau tangles, and consequent neuronal loss begins 10-15 years before any cognitive impairment. In addition to cognitive and behavioral deficits, sensorial abnormalities have been described in AD patients and in some AD transgenic mouse models. Retina can be considered a simple model of the brain, as some pathological changes and therapeutic strategies from the brain may be observed or applicable to the retina. Here we propose new retinal biomarkers that could anticipate the AD diagnosis and help the beginning and the follow-up of possible future treatments. We analyzed retinal tissue of triple-transgenic AD mouse model (3xTg-AD) for the presence of pathological hallmarks during disease progression. We found the presence of amyloid beta plaques, tau tangles, neurodegeneration, and astrogliosis in the retinal ganglion cell layer of 3xTg-AD mice, already at pre-symptomatic stage. Moreover, retinal microglia in pre-symptomatic mice showed a ramified, anti-inflammatory phenotype which, during disease progression, switches to a pro-inflammatory, less ramified one, becoming neurotoxic. We hypothesize retina as a window through which monitor AD-related neurodegeneration process

High resolution spectroscopic analysis of seven giants in the bulge globular cluster NGC 6723

Globular clusters associated with the Galactic bulge are important tracers of stellar populations in the inner Galaxy. High resolution analysis of stars in these clusters allows us to characterize them in terms of kinematics, metallicity, and individual abundances, and to compare these fingerprints with those characterizing field populations. We present iron and element ratios for seven red giant stars in the globular cluster NGC~6723, based on high resolution spectroscopy. High resolution spectra ($R\sim48~000$) of seven K giants belonging to NGC 6723 were obtained with the FEROS spectrograph at the MPG/ESO 2.2m telescope. Photospheric parameters were derived from $\sim130$ FeI and FeII transitions. Abundance ratios were obtained from line-to-line spectrum synthesis calculations on clean selected features. An intermediate metallicity of [Fe/H]$=-0.98\pm0.08$ dex and a heliocentric radial velocity of $v_{hel}=-96.6\pm1.3~km s^{-1}$ were found for NGC 6723. Alpha-element abundances present enhancements of $[O/Fe]=0.29\pm0.18$ dex, $[Mg/Fe]=0.23\pm0.10$ dex, $[Si/Fe]=0.36\pm0.05$ dex, and $[Ca/Fe]=0.30\pm0.07$ dex. Similar overabundance is found for the iron-peak Ti with $[Ti/Fe]=0.24\pm0.09$ dex. Odd-Z elements Na and Al present abundances of $[Na/Fe]=0.00\pm0.21$ dex and $[Al/Fe]=0.31\pm0.21$ dex, respectively. Finally, the s-element Ba is also enhanced by $[Ba/Fe]=0.22\pm0.21$ dex. The enhancement levels of NGC 6723 are comparable to those of other metal-intermediate bulge globular clusters. In turn, these enhancement levels are compatible with the abundance profiles displayed by bulge field stars at that metallicity. This hints at a possible similar chemical evolution with globular clusters and the metal-poor of the bulge going through an early prompt chemical enrichment