Endotoxin (LPS) clearance mechanisms
Circulating endotoxin (lipopolysaccharide [LPS]) is cleared through binding to host LPS-binding proteins, shuttling to lipoproteins, uptake by liver cells, and biochemical inactivation of lipid A. [1][2][3]
LPS binding proteins in plasma
LPS-binding protein (LBP) binds LPS and promotes transfer of LPS to CD14. [4]
LBP also facilitates movement of LPS onto lipoprotein particles, which reduces exposure of LPS to cell-surface signaling complexes. [5]
Soluble CD14 (sCD14) acts as a shuttle for LPS delivered by LBP and can support neutralization in conjunction with high-density lipoprotein (HDL). [6]
Liver uptake by sinusoidal cells and macrophages
Blood-borne LPS is eliminated rapidly by liver sinusoidal endothelial cells (LSECs). [7]
Larger LPS-associated particles are cleared primarily through phagocytic uptake by macrophages, including Kupffer cells in the liver. [7]
Kupffer cells can take up and modify endotoxin, contributing to clearance and detoxification within the liver. [8]
Biochemical inactivation after uptake
LSECs can inactivate internalized LPS through enzymatic processing, including dephosphorylation and deacylation of lipid A. [7]
Acyloxyacyl hydrolase (AOAH) removes secondary fatty acids from the lipid A portion of LPS, which renders LPS immunologically inert. [3]
LPS processing by Kupffer-cell–associated pathways can include deacylation within liver compartments. [9]
Neutralization by bactericidal/permeability-increasing protein (BPI)
Bactericidal/permeability-increasing protein (BPI) binds the lipid A portion of LPS. [10]
BPI neutralizes isolated endotoxin by suppressing LPS bioactivity. [11]
Consequences for systemic LPS bioactivity
Rapid clearance of blood-borne LPS by the liver occurs on the order of minutes in experimental systems. [2]
After clearance from circulation, remaining LPS is rapidly bound to lipoproteins, which neutralize biologic activity. [2]
Important related host “checkpoints”
Multiple host factors cooperate to control the presentation of LPS to receptors, including LBP-mediated transfer, sCD14 shuttling, and lipoprotein sequestration. [2][5][6]
These overlapping mechanisms reduce the duration of bioactive LPS exposure and promote termination of inflammatory signaling. [2][5]