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Cited by 20Immune Response and InflammationBacterial Infections and VaccinesNeuroinflammation and Neurodegeneration Mechanisms

Neisseria meningitidis lipid A mutant LPSs function as LPS antagonists in humans by inhibiting TLR 4-dependent cytokine production

Sprong, Tom, Ley, Peter van der, Abdollahi-Roodsaz, Shahla, Joosten, Leo, Meer, Jos van der, Netea, Mihai, Deuren, Marcel van·2011·Innate Immunity
DOI 10.1177/1753425910383999
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Abstract

Lipopolysaccharide is a major constituent of the outer membrane of Gram-negative bacteria and important in the induction of pro-inflammatory responses. Recently, novel LPS species derived from Neisseria meningitidis H44/76 by insertional inactivation of the lpxL1 and lpxL2 genes have been created with a lipid A portion consisting of five (penta-acylated lpxL1 ) or four (tetra-acylated lpxL2 ) fatty acids connected to the glucosamine backbone instead of six fatty acids in the wild-type LPS. We show that these mutant LPS-types are poor inducers of cytokines (tumor-necrosis factor-α, IL-1β, IL-10, IL-RA) in human mononuclear cells. Both penta- and tetra-acylated meningococcal LPSs were able to inhibit cytokine production by wild-type Escherichia coli or meningococcal LPS. Binding of FITC-labelled E. coli LPS TLR4 transfected Chinese hamster ovary (CHO) cells was inhibited by both mutant LPS-types. Experiments with CHO fibroblasts transfected with human CD14 and TLR4 showed that the antagonizing effect was dependent on the expression of human TLR4. In contrast to the situation in humans, lpxL1 LPS has agonistic activity for cytokine production in peritoneal macrophages of DBA mice, and exacerbated arthritis in murine collagen induced arthritis model. N. meningitidis lipid A mutant LPSs lpxL1 and lpxL2 function as LPS antagonists in humans by inhibiting TLR4-dependent cytokine production but have agonistic activity in mice.

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  • Hexa-acylated LPS potently activates human TLR4/MD2, whereas hypo-acylated tetra- and penta-acylated LPS poorly activate or antagonize human TLR4/MD2 activation driven by hexa-acylated LPS.

    “it has been previously shown that hexa-acylated LPS potently activates human TLR4/MD2, whereas hypo-acylated tetra- and penta-acylated LPS poorly activate or antagonize human TLR4/MD2 activation driven by hexa-acylated LPS22,23.”

    From Gut microbiota-derived hexa-acylated lipopolysaccharides enhance cancer immunotherapy responses (2025) · cites this paper as [23]

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Authors
Sprong, T., Ley, P. V. D., Abdollahi-Roodsaz, S., Joosten, L., Meer, J. V. D., Netea, M., & Deuren, M. V.
Affiliations
  • Radboud University Nijmegen (NL)
  • National Institute for Vaccine Development, Bilthoven, The Netherlands
  • Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Corresponding author
Sprong, Tom
ORCID
Venue
Innate Immunity
Publisher
SAGE Publications
Published
2010-11-18
Volume
17
Issue
6
Pages
517-525
ISSN
  • 1753-4259 (ISSN-L)
  • 1753-4267
DOI
10.1177/1753425910383999
OpenAlex
W2144252752
Cited by
20
References
47
Citations by year
2026: 3 · 2025: 1 · 2020: 2 · 2019: 1 · 2018: 1 · 2016: 2 · 2014: 3 · 2013: 4 · 2012: 2
FWCI
0.95
Type
journal article
Language
en
Open access
closed
Licence
journals.sagepub.com/page/policies/text-and-data-mining-license (tdm)
Locations
  • Innate Immunity (publishedVersion)
  • PubMed (publishedVersion)
  • Radboud Repository (Radboud University) (submittedVersion)
  • Rivm Repository (Netherlands National Institute for Public Health and the Environment) (submittedVersion)
Funders
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Immunology and Microbiology › Microbiology › Bacterial Infections and Vaccines
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Neisseria meningitidis, lipid A, TLR4, cytokine production, TNF-α, interleukin-1, IL-10, CD14, human mononuclear cells, peritoneal macrophages, collagen-induced arthritis
MeSH terms
Acyltransferases, Animals, Arthritis, Experimental, Bacterial Proteins, Cricetulus, Cricetinae, Humans, Leukocytes, Mononuclear, Lipid A, Lipopolysaccharides, Mice, Inbred DBA, Neisseria meningitidis, Transfection, Cytokines, Mutagenesis, Insertional, CHO Cells, Macrophages, Peritoneal, Toll-Like Receptor 4, Mice, Host-Pathogen Interactions

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