Species and mediator specific TLR4 antagonism in primary human and murine immune cells by βGlcN(1↔1)αGlc based lipid A mimetics

Molecular Immunology
Chiranjeevi ChebroluCarsten J Kirschning

Abstract

Immune stimulatory pathogen associated molecular patterns (PAMPs) are major drivers of infection pathology. Infections with Gram-negative bacteria or negatively polar and single stranded RNA influenza virus are prominent causes of morbidity and mortality. Toll-like receptor (TLR) 4 is a major host sensor for both of the two infections. In order to inhibit TLR4 driven immune activation we recently developed synthetic tetra-acylated lipid A mimetics based on a conformationally restricted βGlcN(1↔1)αGlcN disaccharide scaffold (DA-compounds) that antagonized ectopically overexpressed human and murine TLR4/MD-2 complexes. Here we comparatively analyzed human peripheral blood mononuclear cell (hPBMC) and murine bone marrow derived macrophage (mBM) activation upon 30 min of preincubation in vitro with six variably acylated DA-compounds. 16 h subsequent to consequent LPS challenge, we sampled culture supernatants for cytokine and NO concentration analysis. Four compounds significantly inhibited release of both TNF and IL-6 by hPBMCs upon LPS challenge. In contrast, three compounds effectively inhibited mBM production of MIP-2 and KC, and even five of them inhibited IL-6 and NO production. LPS driven like other TLR ligand driven mBM TNF...Continue Reading

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Citations

Jan 6, 2016·Analytical Chemistry·Lindsay J MorrisonJennifer S Brodbelt
Dec 10, 2016·Journal of Agricultural and Food Chemistry·Wen-Juan LiMing-Yong Xie
Apr 6, 2021·Frontiers in Immunology·Holger HeineAlla Zamyatina
Aug 29, 2021·Pharmacology & Therapeutics·Pilar Garcia-VelloAntonio Molinaro

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