Mice expressing high levels of soluble CD14 retain LPS in the circulation and are resistant to LPS‐induced lethality

Abstract

Despite significant progress in understanding the origin of soluble CD14 (sCD14), its physiological function remains largely unknown. Recent research has produced contradictory observations suggesting that sCD14 may have either beneficial or detrimental properties in protection against LPS-induced endotoxin shock. To resolve this controversy and to establish a mouse model suitable for elucidation of the functions of human CD14 (hCD14) in vivo, we generated several lines of transgenic mice bearing different copy numbers of the hCd14 transgene on a murine Cd14 -/-background. The hCD14 was entirely capable of complementing loss of mouse CD14 to mediate cellular responses to LPS. Serum levels of sCD14 in a founder with multiple copies of the transgene were several times higher than in transgenic animals with a single copy of Cd14. Furthermore, mice with high levels of hCD14 were hypo-responsive to LPS and survived a lethal dose of LPS. Further inquiry into the mechanism of the hypo-response to LPS revealed that protection is associated with the higher amounts of circulating LPS. Most of this circulating LPS can be immunoprecipitated with anti-CD14 antibodies. These results suggest that sCD14 blocks circulating LPS by limiting the amount of monocyte-bound LPS and thus reduces inflammatory responses.

IL-10 Enhances MD-2 and CD14 Expression in Monocytes and the Proteins Are Increased and Correlated in HIV-Infected Patients

“…Treatment with anti-CD14 mAb provides therapeutic benefits after in vivo exposure to endotoxin (39). However, mice overexpressing sCD14 retain LPS in the circulation and are resistant to LPS-induced lethality (40). In contrast to sMD-2, an excess of sCD14 inhibits phagocytosis of Gram-negative bacteria (41), which is likely to be due to the fact that mCD14 is a phagocytosing receptor for Gram-negative bacteria, mycobacteria, and apoptotic cells (42,43).…”

Soluble CD14 and CD83 from Human Neonatal Antigen-Presenting Cells Are Inducible by Commensal Bacteria and Suppress Allergen-Induced Human Neonatal Th2 Differentiation

“…CD14 plays a key role in initiating cell activation by a group of bacterially derived structures, such as lipopolysaccharide (LPS) from gram-negative bacteria and peptidoglycan from gram-positive and gram-negative bacteria (15,39). A soluble form of CD14 (sCD14) is present in large amounts in human serum and in breast milk (14,26) and may be an acute-phase protein with the function of protecting against LPS-induced shock (7,21). In addition, sCD14 has immunoregulatory functions, as it interacts with activated human T and B cells, leading to inhibition of interleukin 4 (IL-4), gamma interferon (IFN-␥), and IgE production, respectively (5,34).…”

CD14: A Soluble Pattern Recognition Receptor in Milk

“…Indeed, the range of sCD14 concentrations found in normal and septic humans can significantly decrease monocyte responses to LPS. By competing with mCD14, the soluble form limits the amount of LPS binding to the cells (Jacque et al, 2006) and thereby inhibits LPS-induced cellular activation (Grunwald et al, 1993;Haziot et al, 1994;Schutt et al, 1992). However, in addition to binding bacterial motifs, sCD14 also binds phospholipids, such as phosphatidylinositol and phosphatidylethanolamine, and transfers them to high-density lipoproteins (Yu et al, 1997).…”

“…It also mediates the influx of phospholipids into cells as well as their efflux out of cells and into plasma (Sugiyama & Wright, 2001). By shuttling LPS from mCD14 to plasma lipoproteins (Yu et al, 1997;Kitchens et al, 1999Kitchens et al, , 2001, sCD14 may retain LPS in the circulation and prevent LPS-mediated lethality (Jacque et al, 2006). The suggestion that LPS moves between the membrane and soluble forms of CD14 until an equilibrium is reached and is progressively removed from both forms when plasma lipoproteins are present (Kitchens & Thompson, 2005) may explain the apparent ambiguity in sCD14 function.…”

“…Recombinant sCD14 also protects against mortality in mice treated with LPS (Stelter et al, 1998;Haziot et al, 1995). Furthermore, in transgenic mice expressing different copy numbers of the human CD14 transgene on a murine CD14-/-background, mice with high levels of human CD14 retain LPS in the circulation and prevent its delivery to tissues and organs (Jacque et al, 2006). In so doing, these mice are hyporesponsive to LPS and survive a lethal dose (Jacque et al, 2006).…”