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.

Caspase-4 dimerisation and D289 auto-processing elicit an interleukin-1β-converting enzyme.

The noncanonical inflammasome is a signalling complex critical for cell defence against cytosolic Gram-negative bacteria. A key step in the human noncanonical inflammasome pathway involves unleashing the proteolytic activity of caspase-4 within this complex. Caspase-4 induces inflammatory responses by cleaving gasdermin-D (GSDMD) to initiate pyroptosis; however, the molecular mechanisms that activate caspase-4 and govern its capacity to cleave substrates remain poorly defined.

Lipid-protein interactions regulating the canonical and the non-canonical NLRP3 inflammasome.

The inflammatory response is a complex regulated effector mechanism of the innate immune system that is initiated after tissue injury or infection. The NLRP3 inflammasome is an important initiator of inflammation by regulating the activation of caspase-1, the maturation of pro-inflammatory cytokines and the induction of pyroptotic cell death. Numerous studies demonstrate that the NLRP3 inflammasome could be modulated by lipids, existing a relation between lipids and the activation of different inflammatory processes.

Cardiolipin in Immune Signaling and Cell Death.

Cardiolipin (CL) is a tetra-acylated diphosphatidylglycerol lipid. In physiological conditions, CL presents unsaturated chains and is located in the inner mitochondria membrane (IMM). Dead signals, infection, or disease may change the level of CL saturation and oxidation and cause its translocation to the cytosolic side of the outer mitochondrial membrane (OMM), affecting mitochondrial function and the inflammatory response.

Saturation of acyl chains converts cardiolipin from an antagonist to an activator of Toll-like receptor-4.

Cardiolipins (CLs) are tetra-acylated diphosphatidylglycerols found in bacteria, yeast, plants, and animals. In healthy mammals, CLs are unsaturated, whereas saturated CLs are found in blood cells from Barth syndrome patients and in some Gram-positive bacteria. Here, we show that unsaturated but not saturated CLs block LPS-induced NF-κB activation, TNF-α and IP-10 secretion in human and murine macrophages, as well as LPS-induced TNF-α and IL-1β release in human blood mononuclear cells.

Cationic lipids as one-component vaccine adjuvants: A promising alternative to alum.

Effective vaccine formulations consist of several components: an antigen carrier, the antigen, a stimulator of cellular immunity such as a Toll-like Receptors (TLRs) ligand, and a stimulator of humoral response such as an inflammasome activator. Here, we investigated the immunostimulatory and adjuvant properties of lipopolyamines, cationic lipids used as gene carriers. We identified new lipopolyamines able to activate both TLR2 and TLR4 and showed that lipopolyamines interact with TLRs via a mechanism different from the one used by bacterial ligands, activating a strong type-I IFN response, pro-inflammatory cytokines and IL-1β secretion.

Large supramolecular structures of 33-mer gliadin peptide activate toll-like receptors in macrophages.

Gliadin, an immunogenic protein present in wheat, is not fully degraded by humans and after the normal gastric and pancreatic digestion, the immunodominant 33-mer gliadin peptide remains unprocessed. The 33-mer gliadin peptide is found in human faeces and urine, proving not only its proteolytic resistance in vivo but more importantly its transport through the entire human body. Here, we demonstrate that 33-mer supramolecular structures larger than 220 nm induce the overexpression of nuclear factor kappa B (NF-κB) via a specific Toll-like Receptor (TLR) 2 and (TLR) 4 dependent pathway and the secretion of pro-inflammatory cytokines such as IP-10/CXCL10 and TNF-α.