Ornithine lipid is a partial TLR4 agonist and NLRP3 activator
Year: 2024
Type: article
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.
Source: Cell Reports
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,460
Awards: G1175115578, G188102763, Mining the host-pathogen interface to deliver a drug pipeline for treating intractable and emerging infections, G2130271261, G219434938, G2262748287, G23086486, G2520848295, G279363373, G300979063, G34346518, G3480869486, G425668148, G4526231891, G4997553662, G5080475149, G6435148631, G6847198047, G7084143925, G8170199207, G8784647482, G890572598, Inflammasome inhibitors as new first-in-class anti-inflammatory therapies
OpenAlex ID: W4402886702