PlGF and VEGF-A/PlGF Heterodimer are Crucial for Recruitment and Activation of Immune Cells During Choroid Neovascularization.

Purpose: Recruitment and activation of inflammatory cells, such as retinal microglia/macrophages, in the subretinal space contribute significantly to the pathogenesis of age-related macular degeneration (AMD). This study aims to explore the functional role of vascular endothelial growth factor (VEGF-A), placental growth factor (PlGF) and VEGF-A/PlGF heterodimer in immune homeostasis and activation during pathological laser-induced choroidal neovascularization (CNV). Methods: To investigate these roles, we utilized the PlGF-DE knockin (KI) mouse model, which is the full functional knockout (KO) of PlGF. In this model, mice express a variant of PlGF, named PlGF-DE, that is unable to bind and activate VEGFR-1 but can still form heterodimer with VEGF-A. Results: Our findings demonstrate that, although there is no difference in healthy conditions, PlGF-DE-KI mice exhibit decreased microglia reactivity and reduced recruitment of both microglia and monocyte-macrophages, compared to wild-type mice during laser-induced CNV. This impairment is associated with a reduction in VEGF receptor 1 (VEGFR-1) phosphorylation in the retinae of PlGF-DE-KI mice compared to C57Bl6/J mice. Corroborating these data, intravitreal delivery of PlGF or VEGF-A/PlGF heterodimer in PlGF-DE-KI mice rescued the immune cell response at the early phase of CNV compared to VEGF-A delivery. Conclusions: In summary, our study suggests that targeting PlGF and the VEGF-A/PlGF heterodimer, thereby preventing VEGFR-1 activation, could represent a potential therapeutic approach for the management of inflammatory processes in diseases such as AMD.

Cancer-derived exosomal Alu RNA promotes colorectal cancer progression.

Inflammation plays a crucial role in cancer progression, but the relevance of the inflammasome remains unclear. Alu RNA was the first endogenous nucleic acid shown to activate the NLRP3 (nucleotide-binding domain leucine-rich repeat containing 3) inflammasome. Here, we showed that Alu RNA can induce epithelial-to-mesenchymal transition (EMT) through NLRP3 inflammasome activation and IL-1ß release in colorectal cancer (CRC) cells. Alu RNA is stored, transported and transferred to CRC cells by exosomes. Exosomal Alu RNA promotes tumorigenesis by inducing invasion, metastasis and EMT via NLRP3 inflammasome activation. Consistent with these data, we found that significantly increased Alu RNA expression correlates with the induction of NLRP3 priming in human CRC patients. Furthermore, the level of Alu RNA in circulating exosomes correlates with CRC progression in a preclinical model. These findings reveal the direct involvement of Alu RNA in cancer pathogenesis, and its presence in CRC cell-derived exosomes could be used as a noninvasive diagnostic biomarker.

Allelic inactivation of the pseudoautosomal gene SYBL1 is controlled by epigenetic mechanisms common to the X and Y chromosomes.

On the human long-arm pseudoautosomal region (XqPAR), genes that are subject to inactivation are closely linked with those that escape. Genes subject to inactivation are not only silenced on the inactive X in females, but they are also inactivated on the Y chromosome in males. One of the genes subject to this unusual inactivation pattern is the synaptobrevin-like 1 gene (SYBL1). Previously we showed that its silencing on the inactive X and the Y allele involves DNA methylation. This study explores the molecular events associated with SYBL1 silencing and investigates their relationship. Promoter DNA methylation profiles were determined by bisulfite sequencing and immunoprecipitation experiments demonstrate that chromatin on the repressed Xi and the Y alleles has underacetylated histones H3 and H4 and H3-lysine 9 methylation. In addition, the inactive X and the Y allele were found to have a condensed chromatin conformation. In contrast, the expressed allele shows H3 and H4 acetylation, H3-lysine 4 methylation and a less compacted chromatin conformation. In ICF syndrome, a human disease affecting DNA methylation, SYBL1 escapes from silencing and this correlates with altered patterns of histone methylation and acetylation. Combined, our data suggest that specific combinations of histone methylation and acetylation are involved in the somatic maintenance of permissive and repressed chromatin states at SYBL1. Although it is unclear at present how this allele-specific silencing comes about, the data also indicate that the epigenetic features of the 'Y inactivation' of SYBL1 are mechanistically similar to those associated with X-chromosome inactivation.