Human Scavenger Receptors BI and BII Overexpressed in Murine Abdominal Sepsis Model

Background: Class B scavenger receptors BI (SR-BI) and BII (SR-BII) can bind and internalize lipoproteins and bacteria (our recent work in vitro). However, their roles in vivo in a clinically relevant sepsis model are unknown. Methods: We overexpressed human SR-BI and BII (driven by pLiv-11) in the liver and to a lesser extent in the kidney. We performed cecum ligation and puncture (CLP)-induced sepsis surgery, and followed mice for a 7 d-survival study. We also collected blood, peritoneal lavage fluid, kidney, and liver for organ-specific assessment 24 h after CLP surgery. To examine intracellular translocation of bacteria, we infected mouse primary hepatocytes and proximal tubular cells with Escherichia Coli K 12. Intracellular bacteria were counted. To examine in vivobacterial accumulation, GFP-labeled E. coli was intravenously injected to hSR-BI and BII transgenic and WT mice. Isolated liver, kidney, and adrenal gland were observed under a confocal microscope. Results: hSR-BI and BII transgenic mice had significantly worse survival compared to WT mice (SR-BI vs. WT, 6.3% vs. 33.3%, p = 0.001; SR-BII vs. WT, 6.3% vs. 33.3%, p = 0.001). 24 h after CLP, liver organ injury markers and histological injury score were significantly higher in hSR-B transgenic than WT mice, while the extent of kidney injury was comparable between hSR-B transgenic and WT mice. Systemic inflammatory cytokines were markedly increased in hSR-B transgenic mice; parallel increases were seen in liver mRNA expression, not in kidney. Glucocorticoid production was suppressed, and lipid droplets were diminished in the adrenal cortex of hSR-B transgenic mice. We found more intracellular bacteria inside primary cultured hepatocytes from hSR-B transgenic than WT mice, while the bacterial internalization in kidney of hSR-B transgenic mice was as modest as WT mice. Injection of GFP-labeled E. coli revealed more accumulation of GFP-labeled E. coli in liver parenchyma of SR-B transgenic than WT mice. Conclusion: In summary, our findings suggest hSR-BI and BII overexpression contributes to higher mortality in CLP sepsis by adrenal insufficiency, systemic hyperinflammation, and bacterial invasion in liver. Class B scavenger receptors (SR-BI and SR-BII) may play pivotal roles in corticosterone production, innate immunity, and internalization of bacteria during sepsis. Funding: NIDDK Support, Government Support – Non-U.S.