Ornithine Lipid Activates Both TLR4 and the non-canonical NLRP3 Inflammasome.

Toll-like receptors (TLRs) are proteins that act as the sentinels of mammalian cells by detecting bacteria and viruses motifs such as the phospholipid lipopolysaccharides (LPS) from Gram-negative bacterial membrane, among others. Bacteria like Vibrio cholerae, when grow in phosphate-depleted medium are unable to produce LPS and other phospholipids and therefore increase the synthesis of ornithine lipids (OLs) to keep membrane integrity and survival. We found that, although the huge structural differences between OL and LPS, our immune system is still able to detect OL and trigger immune response through TLR4 and the non-canonical Nucleotide-binding domain and leucine-rich repeat-containing pyrin protein 3 (NLRP3) inflammasome. Similar to LPS, OL induced TLR4-dependent tumor necrosis factor (TNF) α secretion and Nuclear Factor (NF)-κB activation and therefore also elicited the priming of the NLRP3 inflammasome. Moreover, incubation of macrophages with OL causes caspase-dependent cleavage of GSDMD and consequent K+ efflux-dependent NLRP3 activation and IL1β secretion. ### Competing Interest Statement LH-N and PP are co-founders of Viva in vitro diagnostics SL, but declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The other authors declare no competing interests.