The Battle of LPS Clearance in Host Defense vs. Inflammatory Signaling

Abstract

Lipopolysaccharide (LPS) in blood circulation causes endotoxemia and is linked to various disease conditions. Current treatments focus on preventing LPS from interacting with its receptor Toll-like receptor 4 (TLR4) and reducing inflammation. However, our body has a natural defense mechanism: reticuloendothelial cells in the liver rapidly degrade and inactivate much of the circulating LPS within minutes. But this LPS clearance mechanism is not perfect. Excessive LPS that escape this clearance mechanism cause systemic inflammatory damage through TLR4. Despite its importance, the role of reticuloendothelial cells in LPS elimination is not well-studied, especially regarding the specific cells, receptors, and mechanisms involved. This gap hampers the development of effective therapies for endotoxemia and related diseases. This review consolidates the current understanding of LPS clearance, narrates known and explores potential mechanisms, and discusses the relationship between LPS clearance and LPS signaling. It also aims to highlight key insights that can guide the development of strategies to reduce circulating LPS by way of bolstering host defense mechanisms. Ultimately, we seek to provide a foundation for future research that could lead to innovative approaches for enhancing the body's natural ability to clear LPS and thereby lower the risk of endotoxin-related inflammatory diseases, including sepsis.

Keywords: Kupffer cells; LPS; LSECs; clearance; endotoxemia; endotoxin associated diseases; liver; scavenger receptors; sepsis; signaling.

Figure 1

Number of articles published on LPS clearance vs. signaling. A search on NCBI using the keywords “LPS + clearance” and “LPS + signaling” reveals the number of articles published on each topic as of August 29th, 2024. The data underscores the importance of understanding LPS clearance.

Figure 2

Schematic representation of LPS clearance and LPS mediated TLR4 signaling pathways. The balance at the top of the figure indicates the interdependence between LPS clearance and LPS signaling pathways. LPS Clearance: LPS binds to HDL facilitated by LBP, forming an LPS-HDL complex that enters the cell through Stabilin-1 and Stabilin-2 receptors mediated vesicular internalization, leading to inactivation/degradation by lysosomal enzymes. Future research needed is highlighted in red, including the identification of additional scavenger receptors, adaptor proteins, coated pits and vesicles, and other enzymes involved in LPS inactivation/degradation. LPS signaling: LPS stimulation in cells involves a series of interactions with several key proteins, including LBP, CD14, MD-2, TLR4. LBP acts as a carrier that binds directly to LPS and brings it to CD14. CD14 is a glycosylphosphatidylinositol-anchored protein that facilitates the transfer of LPS to the TLR4/MD-2 receptor complex. Subsequently, signals activated by TLR4 can be subdivided into MyD88-dependent, which occurs early and MyD88-independent, which occurs later and uses adaptors TRIF and TRAM. The MyD88-dependent pathway triggers through recruitment of TRAF6 which activates TAK1. TAK1 activates NF-κB by phosphorylation to inhibitory subunit IKKβ. NF-κB translocates to the nucleus and promotes transcription of pro-inflammatory genes (such as TNFα, IL-1β, IL1-α, IL-6, and IL-18). The MyD88-independent pathway depends on TRIF recruitment of RIP1 or TRAF3. TRAF3 activates IRF3 through TBK1 and induces transcription of type I interferons (IFNs) and IFN-inducible genes. Additionally, intracellular LPS either coming from endocytosed bacteria or leaked-out from the endosomes can activate caspase 11 dependent canonical or non-canonical inflammasome pathway. Intracellular LPS can bind to caspase 11 which can activate non-canonical inflammasomes and ultimately Pyroptosis. Similarly, caspase 11 can also activate NLRP3 inflammasomes through caspase 1 which can further proceed the conversion of pro-IL-1β and pro-IL-18 into active IL-1β and IL-18. Created on BioRender.com (accessed on 14 September 2024).

Figure 3

Schematic representation of smooth vs. rough LPS. The smooth LPS phenotype (left) expresses all three components: O-antigen, core oligosaccharide, and lipid A. The O-antigen is depicted as an extended chain attached to the core oligosaccharide. The rough LPS phenotype (right) lacks the O-antigen, showing only the core oligosaccharide and lipid A. Fatty acid chain length (n) and position may vary greatly among different species. Phosphate substitutions (P) are commonly found at C1 and C4′ of both GlcN (2-amino-2-deoxy-D-glucose) units that form the lipid-A moiety. Phosphate substitutions may also be found attached to core or O-antigen units. Created on BioRender.com (accessed on 14 September 2024).