Lipopolysaccharide Recognition in the Crossroads of TLR4 and Caspase-4/11 Mediated Inflammatory Pathways

Abstract

The innate immune response to lipopolysaccharide is essential for host defense against Gram-negative bacteria. In response to bacterial infection, the TLR4/MD-2 complex that is expressed on the surface of macrophages, monocytes, dendritic, and epithelial cells senses picomolar concentrations of endotoxic LPS and triggers the production of various pro-inflammatory mediators. In addition, LPS from extracellular bacteria which is either endocytosed or transfected into the cytosol of host cells or cytosolic LPS produced by intracellular bacteria is recognized by cytosolic proteases caspase-4/11 and hosts guanylate binding proteins that are involved in the assembly and activation of the NLRP3 inflammasome. All these events result in the initiation of pro-inflammatory signaling cascades directed at bacterial eradication. However, TLR4-mediated signaling and caspase-4/11-induced pyroptosis are largely involved in the pathogenesis of chronic and acute inflammation. Both extra- and intracellular LPS receptors—TLR4/MD-2 complex and caspase-4/11, respectively—are able to directly bind the lipid A motif of LPS. Whereas the structural basis of lipid A recognition by the TLR4 complex is profoundly studied and well understood, the atomic mechanism of LPS/lipid A interaction with caspase-4/11 is largely unknown. Here we describe the LPS-induced TLR4 and caspase-4/11 mediated signaling pathways and their cross-talk and scrutinize specific structural features of the lipid A motif of diverse LPS variants that have been reported to activate caspase-4/11 or to induce caspase-4/11 mediated activation of NLRP3 inflammasome (either upon transfection of LPS in vitro or upon infection of cell cultures with intracellular bacteria or by LPS as a component of the outer membrane vesicles). Generally, inflammatory caspases show rather similar structural requirements as the TLR4/MD-2 complex, so that a “basic” hexaacylated bisphosphorylated lipid A architecture is sufficient for activation. However, caspase-4/11 can sense and respond to much broader variety of lipid A variants compared to the very “narrow” specificity of TLR4/MD-2 complex as far as the number and the length of lipid chains attached at the diglucosamine backbone of lipid A is concerned. Besides, modification of the lipid A phosphate groups with positively charged appendages such as phosphoethanolamine or aminoarabinose could be essential for the interaction of lipid A/LPS with inflammatory caspases and related proteins.

TRPV1 modulation of immune response in metastatic breast carcinoma: Enhanced inflammatory response may hinder therapeutic potentials of TRPV1 agonists

“…Furthermore, GA actually enhanced TNF-α secretion in LPS-challenged MLCs of 4TLM and 4THM-injected groups. These results demonstrate that GA may enhance the in ammatory response in the presence of TLR-4 stimulation [25].…”

Tailored Modulation of Cellular Pro-inflammatory Responses With Disaccharide Lipid A Mimetics

“…This has been confirmed also in mouse BMDMs where DLAMs 2 and 5 showed 10-fold higher potency in inducing TNF-α compared to E. coli lipid A and were also more potent than Re -LPS ( Figure 12A ). Monitoring the secretion of IL-1β in TPA-primed THP-1 macrophages revealed an inverted activation profile, with longer-chain αα-GM-DLAM 1 being most active, indicating the involvement of different structural factors in ligand recognition for induction of IL-1β pathway ( Figure 10C ) ( 69 ). Indeed, intracellular LPS-mediated IL-1 release in human monocytic cell lines is dependent on caspase-4/5 which regulates the secretion of inflammasome-activated IL-1β ( 70 , 71 ).…”

New Insights on End-Stage Renal Disease and Healthy Individual Gut Bacterial Translocation: Different Carbon Composition of Lipopolysaccharides and Different Impact on Monocyte Inflammatory Response

“…The non-endotoxic lipid A variants are usually under-acylated, and/or possess longer (16 to 18 carbon atoms) lipid chains and lack at least one of the phosphate groups. The TLR4/MD-2 receptor complex responds to very low concentrations (picomolar magnitudes) of LPS via recognition and binding of distinct structural motifs of lipid A through majorly hydrophobic, but also ionic interactions ( 44 ). In this study, ESRD patients and HV differ in their LPS composition according to the length of the lipid A carbon chains: ESRD patients have more LPS with 12-14-carbons, and less LPS with 18-carbons as compared with healthy individuals.…”