Ornithine lipid is a partial TLR4 agonist and NLRP3 activator.

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.
Competing Interests: Declaration of interests L.H.-N. and P.P. are co-founders of Viva In Vitro Diagnostics. P.P. is scientific advisor of Viva In Vitro diagnostics. K.S. is a co-inventor on patent applications for NLRP3 inhibitors licensed to Inflazome, Ltd., a company headquartered in Dublin, Ireland. Inflazome is developing drugs that target the NLRP3 inflammasome to address unmet clinical needs in inflammatory disease. K.S. served on the scientific advisory board of Inflazome in 2016–2017 and serves as a consultant to Quench Bio (USA) and Novartis (Switzerland).
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)