Biology subjects

Regli, L.

Publications and source records attributed to Regli, L..

4 recordsLinked to original sources

bioRxiv2022

MyD88-TLR4-dependent choroid plexus activation precedes perilesional inflammation and edema in intracerebral hemorrhage

The functional neurological outcome of patients with intracerebral hemorrhage (ICH) strongly relates to the degree of secondary brain injury (ICH-SBI) evolving within days after the initial bleeding. Different mechanisms including the incitement of inflammatory pathways, dysfunction of the blood-brain barrier (BBB), activation of resident microglia, and an influx of blood-borne immune cells, have been hypothesized to contribute to ICH-SBI. Yet, the spatiotemporal interplay of specific inflammatory processes within different brain compartments has not been sufficiently characterized, limiting potential therapeutic interventions to prevent and treat ICH-SBI. Using a whole-blood injection model in mice, we systematically characterized the spatial and temporal dynamics of inflammatory processes after ICH using 7-Tesla magnetic resonance imaging (MRI), spatial RNA sequencing (spRNAseq), functional BBB assessment, and immunofluorescence average-intensity-mapping. We identified a pronounced early response of the choroid plexus (CP) peaking at 12 to 24h, that was characterized by inflammatory cytokine expression, epithelial and endothelial expression of leukocyte adhesion molecules, and the accumulation of leukocytes. In contrast, we observed a delayed secondary reaction pattern at the injection site (striatum) peaking at 96h, defined by gene expression corresponding to perilesional leukocyte infiltration and correlating to the delayed signal alteration seen on MRI. Pathway analysis revealed a dependence of the early inflammatory reaction in the CP on toll-like receptor 4 (TLR4) signaling via myeloid differentiation factor 88 (MyD88). TLR4 and MyD88 knockout mice corroborated this observation, lacking the early upregulation of adhesion molecules and leukocyte infiltration within the CP 24h after whole-blood injection. In conclusion, we report a biphasic brain reaction pattern after ICH with a MyD88-TLR4-dependent early inflammatory response of the CP, preceding inflammation, edema and leukocyte infiltration at the lesion site. Pharmacological targeting of the early CP-activation might harbor the potential to modulate the development of ICH-SBI. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC="FIGDIR/small/506660v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@195554corg.highwire.dtl.DTLVardef@1130d16org.highwire.dtl.DTLVardef@1c03678org.highwire.dtl.DTLVardef@381ff4_HPS_FORMAT_FIGEXP M_FIG C_FIG Akeret, Buzzi et al. characterized the spatiotemporal dynamics after striatal whole blood injection in mice using magnetic resonance imaging (MRI), spatial RNA sequencing (spRNAseq), functional blood-brain barrier (BBB) assessment, and immunofluorescence average intensity mapping (IF). They report a biphasic brain reaction pattern with an early MyD88-TLR4-dependent inflammatory response of the CP, which preceded secondary inflammation and leukocyte infiltration at the perilesional site.

neuroscience↗

bioRxiv2022

Blood oxygenation-level dependent cerebrovascular reactivity imaging as strategy to monitor CSF-hemoglobin toxicity

PurposeCell-free hemoglobin in the cerebrospinal fluid (CSF-Hb) may be one of the main drivers of secondary brain injury after aneurysmal subarachnoid hemorrhage. Haptoglobin scavenging of CSF-Hb has been shown to mitigate cerebrovascular disruption. Using digital subtraction angiography (DSA) and blood oxygenation-level dependent cerebrovascular reactivity imaging (BOLD-CVR) the aim was to assess the acute toxic effect of CSF-Hb on cerebral blood flow and autoregulation, as well as to test the protective effects of haptoglobin. MethodsDSA imaging was performed in eight anesthetized and ventilated sheep (mean weight: 80.4 kg) at baseline, 15, 30, 45 and 60 minutes after infusion of hemoglobin (Hb) or co-infusion with haptoglobin (Hb:Haptoglobin) into the left lateral ventricle. Additionally, 10 ventilated sheep (mean weight: 79.8 kg) underwent BOLD-CVR imaging to assess the cerebrovascular reserve capacity. ResultsDSA imaging did not show a difference in mean transit time or cerebral blood flow. Wholebrain BOLD-CVR compared to baseline decreased more in the Hb group after 15 minutes (Hb vs Hb:Haptoglobin: -0.03 {+/-}0.01 vs -0.01 {+/-}0.02) and remained diminished compared to Hb:Haptoglobin group after 30 minutes (Hb vs Hb:Haptoglobin: -0.03 {+/-}0.01 vs 0.0 {+/-}0.01), 45 minutes (Hb vs Hb:Haptoglobin: -0.03 {+/-}0.01 vs 0.01 {+/-}0.02) and 60 minutes (Hb vs Hb:Haptoglobin: -0.03 {+/-}0.02 vs 0.01 {+/-}0.01). ConclusionIt is demonstrated that CSF-Hb toxicity leads to rapid cerebrovascular reactivity impairment, which is blunted by haptoglobin co-infusion. BOLD-CVR may therefore be further evaluated as a monitoring strategy for CSF-Hb toxicity after aSAH.

neuroscience↗

bioRxiv2021

Molecular atlas of the human brain vasculature at the single-cell level

A broad range of brain pathologies critically relies on the vasculature, and cerebrovascular disease is a leading cause of death worldwide. However, the cellular and molecular architecture of the human brain vasculature remains poorly understood. Here, we performed single-cell RNA sequencing of 599,215 freshly isolated endothelial, perivascular and other tissue-derived cells from 47 fetuses and adult patients to construct a molecular atlas of the developing fetal, adult control and diseased human brain vasculature. We uncover extensive molecular heterogeneity of healthy fetal and adult human brains and across eight vascular-dependent CNS pathologies including brain tumors and brain vascular malformations. We identify alteration of arteriovenous differentiation and reactivated fetal as well as conserved dysregulated pathways in the diseased vasculature. Pathological endothelial cells display a loss of CNS-specific properties and reveal an upregulation of MHC class II molecules, indicating atypical features of CNS endothelial cells. Cell-cell interaction analyses predict numerous endothelial-to-perivascular cell ligand-receptor crosstalk including immune-related and angiogenic pathways, thereby unraveling a central role for the endothelium within brain neurovascular unit signaling networks. Our single-cell brain atlas provides insight into the molecular architecture and heterogeneity of the developing, adult/control and diseased human brain vasculature and serves as a powerful reference for future studies.

neuroscience↗

bioRxiv2019

The HLA Ligand Atlas. A resource of natural HLA ligands presented on benign tissues.

The human leukocyte antigen (HLA) complex controls adaptive immunity by presenting defined fractions of the intracellular and extracellular protein content to immune cells. Here, we describe the HLA Ligand Atlas, an extensive collection of mostly matched HLA-I and -II ligandomes from 225 benign samples (29 tissues, 21 subjects). The initial release covers 51 HLA-I and 86 HLA-II allotypes presenting 89,853 HLA-I- and 140,861 HLA-II ligands. We observe that the immunopeptidomes differ considerably between tissues and individuals on both source protein and HLA-ligand level. 1,407 HLA-I ligands stem from non-canonical genomic regions. We highlight the importance of comparatively analyzing both benign and malignant tissues to inform tumor association, based on a case study in three glioblastoma patients. The resource provides insights into applied and basic immune-associated questions in the context of cancer immunotherapy, infection, transplantation, allergy, and autoimmunity. It is publicly available at www.hla-ligand-atlas.org.

immunology↗