Biology subjects

Solito, E.

Publications and source records attributed to Solito, E..

4 recordsLinked to original sources

bioRxiv2022

Cerebrovascular damage caused by the gut microbe-derived uraemic toxin p-cresol sulfate isprevented by blockade of the epidermal growth factor receptor

Circulating levels of the gut microbe/host co-metabolite p-cresol sulfate (pCS) correlate with cerebrovascular event risk in individuals with chronic kidney disease, but whether this relationship is mechanistic is unclear. We hypothesised that pCS would impair function of the blood-brain barrier (BBB), the primary brain-vasculature interface. We report that pCS exposure impairs BBB integrity in human cells in vitro and both acutely and chronically in mice, enhancing tracer extravasation, disrupting barrier-regulating tight junction components and ultimately affecting whole-brain transcriptomic activity. In vitro and in vivo mechanistic studies showed that pCS activated epidermal growth factor receptor (EGFR) signalling, resulting in matrix metalloproteinase mobilisation and BBB damage. Furthermore, blockade of EGFR prevented the permeabilising effects of serum from haemodialysis patients upon cerebromicrovascular endothelia in vitro. Our results define a pathway linking the co- metabolite pCS with BBB damage and suggest targeting the EGFR may mitigate against cerebrovascular damage in CKD.

systems biology↗

bioRxiv2021

Regulation of blood-brain barrier integrity and cognition by the microbiome-associated methylamines trimethylamine N-oxide and trimethylamine

BackgroundCommunication between the gut microbiota and the brain is primarily mediated via soluble microbe-derived metabolites, but the details of this pathway remain poorly defined. Methylamines produced by microbial metabolism of dietary choline and L-carnitine have received attention due to their proposed association with vascular disease, but their effects upon the cerebrovascular circulation have hitherto not been studied. ResultsHere we use an integrated in vitro/in vivo approach to show that physiologically relevant concentrations of the dietary methylamine trimethylamine N-oxide (TMAO) enhanced blood-brain barrier (BBB) integrity and protected it from inflammatory insult, acting through the tight junction regulator annexin A1. In contrast, the TMAO precursor trimethylamine (TMA) impaired BBB function and disrupted tight junction integrity. Moreover, we show that long-term exposure to TMAO protects murine cognitive function from inflammatory challenge, acting to limit astrocyte and microglial reactivity in a brain region-specific manner. ConclusionOur findings demonstrate the mechanisms through which microbiome-associated methylamines directly interact with the mammalian BBB, with consequences for cerebrovascular and cognitive function.

systems biology↗

bioRxiv2019

Mitochondrial mass governs the extent of T cell senescence

The susceptibility of human CD4+ and CD8+ T cells to senesce differs, with CD8+ T cells acquiring an immunosenescent phenotype faster than their CD4+ T cell compartment. We show here that it is the inherent difference in mitochondrial content that drives this phenotype, with senescent human CD4+ T cells displaying a higher mitochondrial mass. The loss of mitochondria in the senescent human CD8+ T cells has knock-on consequences for nutrient usage, metabolism and function. Mitochondrial dysfunction has been linked to both cellular senescence and ageing, however it is still unclear whether mitochondria play a causal role in senescence. Our data shows that reducing mitochondrial function in human CD4+ T cells, through the addition of low dose rotenone, causes the generation of a CD4+ T cell with a CD8+ -like phenotype. Therefore we wish to propose that it is the inherent metabolic stability that governs the susceptibility to an immunosenescent phenotype.

immunology↗

bioRxiv2018

Estrogen promotes pro-resolving microglial behaviour and phagocytic cell clearance through the actions of annexin A1

Local production of estrogen rapidly follows brain tissue injury, but the role this hormone plays in regulating the response to neural damage or in the modulation of mediators regulating inflammation is in many ways unclear. Using the murine BV2 microglia model as well as primary microglia from wild-type and annexin A1 (AnxA1) null mice, we have identified two related mechanisms whereby estradiol can modulate microglial behaviour in a receptor specific fashion. Firstly, estradiol, via estrogen receptor {beta} (ER{beta}), enhanced the phagocytic clearance of apoptotic cells, acting through increased production and release of the protein AnxA1. Secondly, stimulation of either ER{beta} or the G protein coupled estrogen receptor GPER promoted the adoption of an anti-inflammatory/proresolving phenotype, an action similarly mediated through AnxA1. Together, these data suggest the hypothesis that locally produced estrogen acts through AnxA1 to exert powerful pro-resolving actions, controlling and limiting brain inflammation and ultimately protecting this highly vulnerable organ. Given the high degree of receptor selectivity in evoking these responses, we suggest that the use of selective estrogen receptor ligands may hold therapeutic promise in the treatment of neuroinflammation, avoiding unwanted generalised effects.

neuroscience↗