Stabilin receptors clear LPS and control systemic inflammation

Authors

Fatima Cabral, University of Nebraska–Lincoln
Mustafa Al-Rahem, The Ohio State University Wexner Medical Center
John Skaggs, The Ohio State University Wexner Medical Center
Thushara A. Thomas, The Ohio State University Wexner Medical Center
Naresh Kumar, The Ohio State University
Qian Wu, The Ohio State University
Paolo Fadda, The Ohio State University Comprehensive Cancer Center
Lianbo Yu, The Ohio State University
John M. Robinson, The Ohio State University
Jonghan Kim, University of Massachusetts Lowell
Ekta Pandey, University of Nebraska–LincolnFollow
Xinghui Sun, University of Nebraska–LincolnFollow
Wael N. Jarjour, The Ohio State University Wexner Medical Center
Murugesan V.S. Rajaram, The Ohio State University
Edward N. Harris, University of Nebraska-LincolnFollow
Latha P. Ganesan, The Ohio State University Wexner Medical Center

Document Type

Article

Date of this Version

11-19-2021

Citation

iScience 24, 103337, November 19, 2021

doi:10.1016/ j.isci.2021.103337

Comments

OPEN ACCESS

Abstract

Lipopolysaccharides (LPSs) cause lethal endotoxemia if not rapidly cleared from blood circulation. Liver sinusoidal endothelial cells (LSEC) systemically clear LPS by unknown mechanisms. We discovered that LPS clearance through LSEC involves endocytosis and lysosomal inactivation via Stabilin-1 and 2 (Stab1 and Stab2) but does not involve TLR4. Cytokine production was inversely related to clearance/endocytosis of LPS by LSEC. When exposed to LPS, Stabilin double knockout mice (Stab DK) and Stab1 KO, but not Stab2 KO, showed significantly enhanced systemic inflammatory cytokine production and early death compared with WT mice. Stab1 KO is not significantly different from Stab DK in circulatory LPS clearance, LPS uptake and endocytosis by LSEC, and cytokine production. These data indicate that (1) Stab1 receptor primarily facilitates the proactive clearance of LPS and limits TLR4-mediated inflammation and (2) TLR4 and Stab1 are functionally opposing LPS receptors. These findings suggest that endotoxemia can be controlled by optimizing LPS clearance by Stab1.