Exploring the LPS/TLR4 signal pathway with small molecules

Abstract

The identification of the bacterial endotoxin receptors for innate immunity, most notably TLR4 (Toll-like receptor 4), has sparked great interest in therapeutic manipulation of the innate immune system. In the present mini-review, several natural and synthetic molecules that modulate the TLR4-mediated LPS (lipopolysaccharide) signalling in animals and humans are considered, and their mechanisms of action are discussed. The process of LPS sensing and signal amplification in humans is based on the sequential action of specific receptors situated in the extracellular side of the innate immunity cells, which bind and transfer LPS to TLR4: LBP (LPS-binding protein), CD14, MD-2 (myeloid differentiation protein 2). We classified the compounds active on TLR4 pathway depending on the specific molecular targets (LPS, LBP, CD14, MD-2 or TLR4). Small molecules developed by our group are described that inhibit LPS-stimulated TLR4 activation by selectively targeting the LPS-CD14 interaction. These compounds have an interesting antiseptic shock, anti-inflammatory and anti-neuropathic pain activity in vivo.

TRPV1 Deletion Enhances Local Inflammation and Accelerates the Onset of Systemic Inflammatory Response Syndrome

“…In addition, TLR4 could sensitize TRPV1 via protein kinase C activation (53). Although these pieces of evidence suggest a sensing mechanism for bacterial infection in sensory nerves, we could not find differences in the mRNA expression of TLR4 or in molecules involved in the pathogen recognition mediated by TLR4 and TLR4 signaling such as CD14, TREM1, and TREM2 (52)(53)(54)(55)(56). This suggests that TRPV1 does not interfere with TLR4 functioning, but rather reinforces the idea that TRPV1 regulates bacterial killing instead.…”

“…In this study, we show reduced levels of TAC-1 mRNA in CLP TRPV1KO when compared with CLP WT peritoneal inflammatory cells. SP is suggested to modulate immune cell function and inflammation via a range of mechanisms (28,29,55,57). This article shows for the first time, to our knowledge, that SP mediates TRPV1 protection by positively regulating macrophage phagocytosis via NK 1 receptor activation.…”

Chaetoglobosin Fex from the Marine-Derived Endophytic Fungus Inhibits Induction of Inflammatory Mediators via Toll-Like Receptor 4 Signaling in Macrophages

“…TLR4, one of the gateways to inflammatory signaling in the macrophage, can start the inflammation response, thus has sparked great interest in therapeutic manipulation. 31) In an effort to search for novel TLR4 signaling regulators from endophytic metabolites, more than 100 natural products were tested for their ability to reduce inflammatory mediators' production from LPS-stimulated RAW264.7 macrophages. Although Cha Fex was isolated previously, to the best of our knowledge this is the first time this compound was shown to reduce inflammatory mediators production.…”

Endotoxin Effects on Cardiac and Renal Functions and Cardiorenal Syndromes

“…Indeed, TLR4 remains the only TLR member that does not directly connect its respective ligand and requires a co-receptor; in fact the MD-2 protein is necessary for LPS recognition and is directly implicated in the activation of the receptor complex [23]. The transfer of LPS from CD14 to MD-2, coupled with the association of MD-2 to TLR4, is mandatory for downstream signaling activation [26], which is mediated by toll/interleukin-1 receptor.…”