Modulating LPS Signal Transduction at the LPS Receptor Complex with Synthetic Lipid A Analogues

Abstract

Sepsis, defined as a clinical syndrome brought about by an amplified and dysregulated inflammatory response to infections, is one of the leading causes of death worldwide. Despite persistent attempts to develop treatment strategies to manage sepsis in the clinical setting, the basic elements of treatment have not changed since the 1960s. As such, the development of effective therapies for reducing inflammatory reactions and end-organ dysfunction in critically ill patients with sepsis remains a global priority. Advances in understanding of the immune response to sepsis provide the opportunity to develop more effective pharmaceuticals. This article details current information on the modulation of the lipopolysaccharide (LPS) receptor complex with synthetic Lipid A mimetics. As the initial and most critical event in sepsis pathophysiology, the LPS receptor provides an attractive target for antisepsis agents. One of the well-studied approaches to sepsis therapy involves the use of derivatives of Lipid A, the membrane-anchor portion of an LPS, which is largely responsible for its endotoxic activity. This article describes the structural and conformational requirements influencing the ability of Lipid A analogues to compete with LPS for binding to the LPS receptor complex and to inhibit the induction of the signal transduction pathway by impairing LPS-initiated receptor dimerization.

The CD14 (−159 C/T) SNP is associated with sCD14 levels and allergic asthma, but not with CD14 expression on monocytes

“…Excluding the hepatocyte origin, monocytes are the most likely cell source of sCD14. Down-modulation of mCD14 in monocytes from AA does not fit with either its shedding 2 , 6 , 7 or the release of mCD14-enriched vesicles [ http://exocarta.org/gene_summary?gene_id=12475 ] from these cells, because both processes should lead to a higher number of sCD14 molecules in the extracellular compartment, as happen during the acute phase 15 , 16 , 46 , 47 . However, patients in our study are in a chronic phase, where there is no relationship between monocyte count and sCD14 or mCD14-sCD14 correlation 16 .…”

“…Innate defences also rely on pattern recognition receptors, such as toll-like receptors (TLRs), capable of detecting pathogen-associated molecular patterns (PAMPs). Lipopolysaccharide (LPS) is a PAMP that interacts with CD14 (monocytes, macrophages, and neutrophils) 2 , a receptor whose gene has been linked to asthma/allergy 3 . CD14 transfers LPS to the TLR4-MD2 complex, which induces the secretion of a set of cytokines (IL-12/IL-18) that act as an innate-adaptive bridge and favour the TH 1 differentiation 4 .…”

“…Membrane-bound CD14 (mCD14) is released to the medium as soluble CD14 (sCD14) 2 , 6 , 7 , which either potentiates the response to LPS in macrophages by inducing the release of proinflammatory cytokines 8 , or has a protective role by transferring LPS to lipoproteins 9 . sCD14 is released from monocytes through a process enhanced by LPS, IL-6 and IL-1β 6 , but decreased by interferon-γ (IFN-γ) and IL-4 10 .…”

“…sCD14 inversely correlates with IL-4 11 , but positively with the number of sputum eosinophils 12 . Moreover, plasma sCD14 is a biomarker of ongoing or acute immune responses 2 , 13 . Thus, children with asthma exacerbations display augmented sCD14 levels compared to the recovery phase 14 , 15 , whereas adult asthmatics have higher amounts in sputum than healthy subjects 12 .…”

Abrogating ClC-3 Inhibits LPS-induced Inflammation via Blocking the TLR4/NF-κB Pathway

“…LPS-induced systemic inflammation or endotoxemia is a well-accepted and validated model of systemic inflammatory response syndrome characterized by pathological changes that strongly resemble sepsis1819. LPS mediates the activation of endothelial cells, smooth muscle cells, fibroblasts, epithelial cells and monocytes,and induces inflammatory cytokines, chemokines, growth factors and other factors, such as interleukins and tumor necrosis factor20.…”