Patterson, A. P. | Search bioRxiv

bioRxiv2026

Different functions of human scavenger receptors BI and BII overexpressed in a murine abdominal sepsis model

Class B scavenger receptors BI (SR-BI) and BII (SR-BII) internalize lipoproteins but also bind and internalize bacteria. Their roles in sepsis are unknown. We overexpressed human SR-BI and BII in the liver and kidney as well as bone marrow-derived macrophages, and then performed cecal ligation and puncture (CLP) surgery. SR-BI and BII transgenic mice had significantly worse survival compared to WT mice. 24 h after CLP, liver injury markers and histological damage were prominent in both SR-BI and BII transgenic mice, whereas kidney damage was similar. Systemic inflammatory cytokines were markedly increased in SR-BI and BII transgenic mice; parallel increases were seen in liver mRNA expression, not in the kidney. The highest degree of neutrophil infiltration was observed in the liver of SR-BI. Human SR-BI and BII dramatically decreased bacterial accumulation in the liver. Green fluorescence protein-labeled E. coli were efficiently phagocytosed in hepatic macrophages of SR-BI and BII transgenic mice; phagocytosis was more prominent in SR-BII transgenic mice. Finally, human SR-BI overexpression reduced systemic HDL-C level, eliminated adrenal cortex lipid droplets, and dampened the systemic increase of corticosterone after CLP. Supplementation with glucocorticoid and mineralocorticoid improved survival in SR-BI, but not SR-BII, transgenic mice after CLP. In summary, our findings suggest human SR-BI and BII overexpression contributes to higher mortality after CLP by excessive inflammatory response due to adrenal insufficiency (SR-BI) or hyperactive phagocytosis (SR-BII) in the liver.

pathology↗

bioRxiv2024

Monosynaptic ventral tegmental area glutamate projections to the locus coeruleus enhance aversive processing

Distinct excitatory synaptic inputs to the locus coeruleus (LC) modulate behavioral flexibility. Here we identify a novel monosynaptic glutamatergic input to the LC from the ventral tegmental area (VTA). We show robust VTA axonal projections provide direct glutamatergic transmission to LC. Despite weak synaptic summation, optogenetic activation of these axons enhances LC tonic firing and facilitates real-time and conditioned aversive behaviors. We hypothesized this projection may modulate synaptic integration with other excitatory inputs. We then used coincident VTA-LC photostimulation with local electrical stimulation and observed enhanced LC burst induction. To determine whether this integration also occurs in vivo, we took an analogous approach measuring reward-seeking behavior during unpredictable probabilistic punishment. Here, glutamatergic VTA-LC photostimulation during a concurrent noxious stimulus did not delay reward-seeking behavior, but increased probability of task failure. Together, we identified a novel VTA-LC glutamatergic projection that drives concurrent synaptic summation during salient stimuli to promote behavioral avoidance.

neuroscience↗