Stabilin Receptors Clear LPS and Control Systemic Inflammation

Abstract

Lipopolysaccharides (LPS), remnants of Gram-negative bacterial cell membranes, cause lethal endotoxemia if not rapidly cleared from blood circulation.  Liver sinusoidal endothelial cells (LSEC) systemically clear LPS by unknown mechanism(s).  We discovered that LPS clearance through LSEC involves endocytosis via Stabilin scavenger receptors (Stab-1 and -2) through lysosomal inactivation.  We determined that LPS was lower in the circulation of wild-type (WT) mice than Stab-1 and -2 KO mice, and endocytic uptake was higher in LSEC from WT than in Stab-1 and -2 KO.  Stab-1 and -2 KO showed enhanced systemic inflammatory cytokine production and early death compared to WT mice when exposed to LPS.  Although LSEC expresses innate immune mediator TLR4, LPS clearance does not use this functional TLR4 system.  These data suggest that Stabilin receptors facilitate the proactive clearance of LPS, and control TLR4 mediated inflammation.  The findings suggest a means of minimizing endotoxemia by optimizing Stabilin-dependent systemic LPS clearance

Keywords: LPS, liver, endotoxin, Liver sinusoidal endothelial cell, Kupffer cell, endotoxemia, systemic inflammation, endocytosis, clearance, Sepsis, gut, gram negative bacteria, innate immunity, effector functions, lysosomes, LAMP-1