Ornithine lipid is a partial TLR4 agonist and NLRP3 activator

  1. Pizzuto, Malvina
  2. Hurtado-Navarro, Laura 1
  3. Molina-Lopez, Cristina 1
  4. Soubhye, Jalal
  5. Gelbcke, Michel
  6. Rodriguez-Lopez, Silvia
  7. Ruysschaert, Jean-Marie
  8. Schroder, Kate
  9. Pelegrin, Pablo 1
  1. 1 Universidad de Murcia
    info

    Universidad de Murcia

    Murcia, España

    ROR https://ror.org/03p3aeb86

Revista:
Cell Reports

ISSN: 2211-1247

Any de publicació: 2024

Volum: 43

Número: 10

Pàgines: 114788

Tipus: Article

DOI: 10.1016/J.CELREP.2024.114788 GOOGLE SCHOLAR lock_openAccés obert editor

Altres publicacions en: Cell Reports

Resum

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.

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