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Published on: May 2, 2018
Modulatory effects of sCD14 and LBP on LPS-host cell interactions
Richard L Kitchens1, Patricia A Thompson
1Division of Infectious Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9113, USA. richard.kitchens@UTSouthwestern.edu
Abstract:
LPS binding protein (LBP) and CD14 play key roles in promoting innate immunity to Gram-negative bacteria by transferring LPS to the signaling receptor complex, MD-2/Toll-like receptor 4 (TLR4). LBP and soluble CD14 (sCD14) can also inhibit responses to LPS by mechanisms that depend on their concentration and environment; during acute inflammation and infection, their concentrations increase in plasma and extravascular fluids. Whereas low concentrations of LBP enhance responses to LPS, high LBP concentrations can inhibit LPS bioactivity in vitro and in vivo. sCD14 also inhibits cell responses by diverting LPS from membrane-bound CD14 (mCD14) and by promoting LPS efflux from cell-surface mCD14 and transferring it to plasma lipoproteins. In vivo studies support the hypothesis that sCD14 has systemic anti-inflammatory effects, whereas in the tissues it may have pro-inflammatory effects that increase resistance to bacteria. Likewise, LBP increases resistance to Gram-negative bacteria by rapidly triggering pro-inflammatory responses to LPS. Thus, the dual stimulatory and inhibitory mechanisms of sCD14 and LBP may benefit the infected host by promoting inflammation in local sites, where it is needed, while at the same time preventing potentially detrimental systemic responses to LPS.
Insights
LPS binding protein (LBP) and soluble CD14 (sCD14) have dual roles in innate immunity. They can enhance or inhibit responses to bacterial lipopolysaccharide (LPS) to protect the host.
Area of Science:
- Immunology
- Microbiology
- Biochemistry
Background:
- LPS binding protein (LBP) and CD14 are crucial for innate immunity against Gram-negative bacteria.
- They facilitate lipopolysaccharide (LPS) transfer to the MD-2/Toll-like receptor 4 (TLR4) signaling complex.
- Both LBP and soluble CD14 (sCD14) exhibit concentration-dependent dual roles, acting as both stimulators and inhibitors of LPS responses.
Purpose of the Study:
- To elucidate the complex, dual mechanisms of LBP and sCD14 in modulating innate immune responses to LPS.
- To understand how varying concentrations and environments influence the stimulatory and inhibitory functions of LBP and sCD14.
- To investigate the in vivo and in vitro effects of LBP and sCD14 on LPS bioactivity and host defense.
Main Methods:
- In vitro and in vivo studies were conducted.
- Concentration-dependent effects of LBP and sCD14 on LPS bioactivity were assessed.
- Mechanisms of LPS transfer, diversion, and efflux involving CD14 and LBP were investigated.
Main Results:
- High LBP concentrations inhibit LPS bioactivity, while low concentrations enhance it.
- sCD14 inhibits cell responses by diverting LPS from membrane-bound CD14 (mCD14) and promoting LPS efflux.
- In vivo, sCD14 demonstrates systemic anti-inflammatory effects, but can be pro-inflammatory in tissues, enhancing bacterial resistance.
- LBP enhances resistance to Gram-negative bacteria by triggering pro-inflammatory LPS responses.
Conclusions:
- LBP and sCD14 possess dual stimulatory and inhibitory functions in innate immunity.
- These dual mechanisms may protect the host by promoting localized inflammation while preventing systemic LPS-induced damage.
- The findings highlight the intricate regulation of immune responses to bacterial components by LBP and sCD14.
