Structural variants of Salmonella Typhimurium lipopolysaccharide induce less dimerization of TLR4/MD-2 and reduced pro-inflammatory cytokine production in human monocytes

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Title: Structural variants of Salmonella Typhimurium lipopolysaccharide induce less dimerization of TLR4/MD-2 and reduced pro-inflammatory cytokine production in human monocytes
Authors: Aldapa-Vega, G
Moreno-Eutimio, MA
Berlanga-Taylor, A
Jiménez-Uribe, AP
Nieto-Velazquez, G
López-Ortega, O
Mancilla-Herrera, I
Cortés-Malagón, EM
Gunn, JS
Isibasi, A
Wong-Baeza, I
López-Macías, C
Pastelin-Palacios, R
Item Type: Journal Article
Abstract: Salmonella enterica serovar Typhimurium (S. Typhimurium) changes the structure of its lipopolysaccharide (LPS) in response to the environment. The two main LPS variants found in S. Typhimurium correspond to LPS with a hepta-acylated lipid A (LPS 430) and LPS with modified phosphate groups on its lipid A (LPS 435). We have previously shown that these modified LPS have a lower capacity than wild type (WT) LPS to induce the production of pro-inflammatory cytokines in mice. Nevertheless, it is not know if LPS 430 and LPS 435 could also subvert the innate immune responses in human cells. In this study, we found that LPS 430 and LPS 435 were less efficient than WT LPS to induce the production of pro-inflammatory cytokines by human monocytes, in addition we found a decreased dimerization of the TLR4/MD-2 complex in response to LPS 430, suggesting that structurally modified LPS are sensed differently than WT LPS by this receptor; however, LPS 430 and 435 induced similar activation of the transcription factors NF-κB p65, IRF3, p38 and ERK1/2 than WT LPS. Microarray analysis of LPS 430- and LPS 435-activated monocytes revealed a gene transcription profile with differences only in the expression levels of microRNA genes compared to the profile induced by WT LPS, suggesting that the lipid A modifications present in LPS 430 and LPS 435 have a moderate effect on the activation of the human TLR4/MD-2 complex. Our results are relevant to understand LPS modulation of immune responses and this knowledge could be useful for the development of novel adjuvants and immunomodulators.
Issue Date: 5-Apr-2019
Date of Acceptance: 7-Mar-2019
URI: http://hdl.handle.net/10044/1/68736
ISSN: 0161-5890
Publisher: Elsevier
Journal / Book Title: Molecular Immunology
Copyright Statement: This paper is embargoed until publication. Once published it will be available fully open access.
Sponsor/Funder: Medical Research Council (MRC)
Medical Research Council (MRC)
Medical Research Council
Funder's Grant Number: MR/L01632X/1
MR/L01632X/1
MEDBIO UK
Keywords: 1107 Immunology
Immunology
Publication Status: Accepted
Embargo Date: publication subject to indefinite embargo
Appears in Collections:Epidemiology, Public Health and Primary Care



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