De Nolf, C. | Search bioRxiv

bioRxiv2024

Newly discovered base barrier cells provide compartmentalization of choroid plexus, brain and CSF

The choroid plexus (ChP) is a highly understudied structure of the central nervous system (CNS). The structure hangs in the brain ventricles, is composed of an epithelial cell layer, which produces the cerebrospinal fluid (CSF) and forms the blood-CSF barrier. It encapsulates a stromal mix of fenestrated capillaries, fibroblasts and a broad range of immune cells. Here, we report that the ChP base region harbors unique fibroblasts that cluster together, are connected by tight junctions and seal the ChP stroma from brain and CSF, thereby forming ChP base barrier cells (ChP BBCs). ChP BBCs are derived from meningeal mesenchymal precursors, arrive early during embryonic development, are maintained throughout life and are conserved across species. Moreover, we provide transcriptional profiles and key markers to label ChP BBCs and observe a striking transcriptional similarity with meningeal arachnoid barrier cells (ABCs). Finally, we provide evidence that this fibroblast cluster functions as a barrier to control communication between CSF and the ChP stroma and between the latter and the brain parenchyma. Moreover, loss of barrier function was observed during an inflammatory insult. Altogether, we have identified a novel barrier that provides functional compartmentalization of ChP, brain and CSF. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/601696v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@181e787org.highwire.dtl.DTLVardef@1875f33org.highwire.dtl.DTLVardef@7b2bcdorg.highwire.dtl.DTLVardef@78baa6_HPS_FORMAT_FIGEXP M_FIG Newly discovered base barrier cells provide compartmentalization of choroid plexus, brain and CSF The choroid plexus (ChP) hangs in the brain ventricles and is composed of an epithelial cell layer which produces the cerebrospinal fluid (CSF) and forms the blood-CSF barrier. The ChP epithelial cells are continuous with the ependymal cells lining the ventricle wall. At this base region, we identified and characterized a novel subtype of fibroblasts coined the ChP base barrier cells (BBCs). ChP BBCs express tight junctions (TJs), cluster together and seal the ChP stroma from CSF and brain parenchyma. The subarachnoid space (SAS) CSF penetrates deep into choroid plexus invaginations where it is halted by ChP BBCs. Abbreviations: E9-16.5 (embryonic day 9-16.5); P1-4 (postnatal day 1-4). C_FIG

neuroscience↗

bioRxiv2022

Nuanced role for dendritic cell intrinsic IRE1 RNase in the regulation of antitumor adaptive immunity.

The IRE1/XBPls axis of the unfolded protein response (UPR) plays divergent roles in dendritic cell (DC) biology in steady state versus tumor contexts. Whereas tumor associated DCs show dysfunctional IRE1/XBP1s activation that curtails their function, the homeostasis of conventional type 1 DCs (cDC1) in tissues requires intact IRE1 RNase activity. Considering that cDC1s are key orchestrators of antitumor immunity, it is relevant to understand the functional versus dysfunctional roles of IRE1/XBP1s in tumor DC subtypes. Here, we show that cDC1s constitutively activate IRE1 RNase within subcutaneous B16 melanoma and MC38 adenocarcinoma tumor models. Mice lacking XBP1s in DCs display increased melanoma tumor growth, reduced T cell effector responses and accumulation of terminal exhausted CD8+ T cells. Transcriptomic studies revealed that XBP1 deficiency in tumor cDCls decreased expression of mRNAs encoding XBPls and regulated IRE1 dependent decay (RIDD) targets. Finally, we find that the dysregulated melanoma growth and impaired T cell immunity noticed in XBP1 deficient mice are attributed to RIDD induction in DCs. This work indicates that IREl RNase activity in melanoma/MC38-associated DCs fine tunes aspects of antitumor immunity independently of XBP1s, revealing a differential role for the UPR axis that depends on the DC subtype and cancer model.

immunology↗