2. Academic Validation
  3. Ornithine lipid is a partial TLR4 agonist and NLRP3 activator

Ornithine lipid is a partial TLR4 agonist and NLRP3 activator

  • Cell Rep. 2024 Oct 22;43(10):114788. doi: 10.1016/j.celrep.2024.114788.
Malvina Pizzuto 1,  Laura Hurtado-Navarro 2,  Cristina Molina-Lopez 2,  Jalal Soubhye 3,  Michel Gelbcke 3,  Silvia Rodriguez-Lopez 2,  Jean-Marie Ruysschaert 4,  Kate Schroder 5,  Pablo Pelegrin 6
Affiliations

Affiliations

  • 1 Molecular Inflammation Group, Biomedical Research Institute of Murcia (IMIB-Arrixaca), 30120 Murcia, Spain; Structure and Function of Biological Membranes Laboratory, Université Libre de Bruxelles, 1050 Brussels, Belgium; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4067, Australia. Electronic address: m.pizzuto@uq.edu.au.
  • 2 Molecular Inflammation Group, Biomedical Research Institute of Murcia (IMIB-Arrixaca), 30120 Murcia, Spain.
  • 3 Department of Pharmacognosy, Bioanalysis and Drug Discovery, Faculty of Pharmacy, Université Libre De Bruxelles, 1050 Brussels, Belgium.
  • 4 Structure and Function of Biological Membranes Laboratory, Université Libre de Bruxelles, 1050 Brussels, Belgium.
  • 5 Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4067, Australia.
  • 6 Molecular Inflammation Group, Biomedical Research Institute of Murcia (IMIB-Arrixaca), 30120 Murcia, Spain; Department of Biochemistry and Molecular Biology B and Immunology, Faculty of Medicine, University of Murcia, 30120 Murcia, Spain.
PMID: 39340778 DOI: 10.1016/j.celrep.2024.114788
Abstract

Gram-negative Bacterial lipopolysaccharides (LPSs) trigger inflammatory reactions through Toll-like Receptor 4 (TLR4) and prime myeloid cells for inflammasome activation. In phosphate-limited environments, bacteria reduce LPS and Other phospholipid production and synthesize phosphorus-free alternatives such as amino-acid-containing lipids like the ornithine lipid (OL). This adaptive strategy conserves phosphate for Other essential cellular processes and enhances Bacterial survival in host environments. While OL is implicated in Bacterial pathogenicity, the mechanism is unclear. Using primary murine macrophages and human mononuclear cells, we elucidate that OL activates TLR4 and induces potassium efflux-dependent nucleotide-binding domain and leucine-rich repeat-containing pyrin protein 3 (NLRP3) activation. OL upregulates the expression of NLRP3 and pro-interleukin (IL)-1β and induces cytokine secretion in primed and unprimed cells. By contrast, in the presence of LPS, OL functions as a partial TLR4 Antagonist and reduces LPS-induced cytokine secretion. We thus suggest that in phosphate-depleted environments, OL replaces LPS Bacterial immunogenicity, while constitutively present OL may allow bacteria to escape immune surveillance.

Keywords

CP: Immunology; CP: Microbiology; IL-1β; NLRP3; TLR; Toll-like receptor; bacteria; caspase; inflammasome; ionizable lipid; lipopolysaccharide; ornithine lipids.

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