Toll-like receptors are major members of the Pattern Recognition Receptors (PRRs) from the innate immune system, which recognize bacterial or viral components. It was suggested that those receptors, that usually recognized molecular patterns characteristic of pathogens, are activated by lipid and protein ligands aggregated into particles and structurally different from the natural ligands. We will illustrate this aspect with two examples:
-It was recently shown that cationic liposomes1, commonly used as nanoparticles engineered to transport active molecules, do activate innate immunity cascades through recognition of a Toll-like receptor mechanism dependent on NF-κB, AP-1, and IRF3 transcription factors as evidenced by cytokine secretion (TNF-α, IL-12, IFN-β, IP-10) and up-regulation of the expression of CD80 and CD86 in murine and human dendritic cells. It is the first example of a drug transporter that turns on into an immunomodulator.
-Amyloidoses are a set of human diseases characterized by the deposition of aggregated proteins in a variety of tissues and organs. Strikingly, despite their different sequences, all these proteins form similar deposits sharing the same morphology and consisting of unbranched fibrils.
We observed2 that aggregated proteins (fibrils) but not monomers or insoluble aggregates, were able to activate pro-inflammatory cytokine secretion through specific recognition of TLR receptors. Since fibrils adopt a cross-β structure, enriched in parallel β-sheet structures, while monomers adopt a helical structure and insoluble aggregates an anti-parallel β-sheet structure, the cross-β motif of the amyloid fibrils found in all amyloid fibrils may constitute a generic pattern sensed as a signal of danger by innate system.
It is hard to believe that molecules which are so different from natural ligands do activate receptors the same way natural ligands do. How lipid and protein aggregates made of a large number of molecules activate pattern recognition receptors is still unknown but it is very likely that it proceeds via a mechanism quite different from what has been described so far for monomeric natural ligands. Implications in nanotechnologies and nanomedicine will be briefly discussed.