Synthetic molecules and functionalized nanoparticles targeting the LPS-TLR4 signaling: A new generation of immunotherapeutics

Abstract

Toll-like receptor 4 (TLR4), the receptor of bacterial endotoxins in mammalians, plays a pivotal role in the induction of innate immunity and inflammation. TLR4 activation by bacterial lipopolysaccharide (LPS) is achieved by the coordinate and sequential action of three other proteins, the lipopolysaccharide binding protein (LBP), the cluster differentiation antigen CD14, and the myeloid differentiation protein (MD-2) receptors, that bind LPS and present it in a monomeric form to TLR4 by forming the activated [TLR4·MD-2·LPS]2 complex. Small molecules and nanoparticles active in modulating the TLR4 signal by targeting directly the MD-2·TLR4 complex or by interfering in other points of the TLR4 signaling are presented in this paper. These compounds have great pharmacological interest as vaccine adjuvants, immunotherapeutics, anti-sepsis, and anti-inflammatory agents.

Titanium dioxide nanoparticles stimulate sea urchin immune cell phagocytic activity involving TLR/p38 MAPK-mediated signalling pathway

“…In this study, we found that TiO 2 NPs cause an increase in the expression of TLR gene and in the levels of the related protein in immune cells of Paracentrotus lividus . This result is in agreement with recent reports highlighting that TLR4 mediates the uptake of some engineered nanoparticles and small molecules in mammals, including TiO 2 NPs 34 35 36 .…”

“…Since immune cells first interact with the physical features of particles, these properties must necessarily have an important role in the recognition of the non-self-matter. Authors support the idea that small molecules and nanoparticles can bind directly the MD-2-TLR4 complex, excluding receptors (LBP, CD14) upstream the canonical LPS sequential recognition; alternatively, they can interfere in other points of the TLR4 signalling 34 . Typically, TLR4 activation triggers a signalling cascade leading to the activation of MAPKs (p38 MAPK, ERK, JNK), resulting in the increased expression and maintenance of a few pro-inflammatory cytokine genes, including IL-6, IL-12, TNF-α 38 .…”

“…As well known, macrophages activate a wide range of PRR including TLRs, which enable the detection of conserved microbial cell wall component, such as LPS, lipoproteins and glycolipids 14 . For example, LPS induce TLR4 activation by a coordinate and sequential action of three other proteins (the lipopolysaccharide binding protein LBP, the cluster differentiation antigen CD14, the myeloid differentiation protein MD-2 receptors) that bind LPS in the monomeric form and present it, as a complex, to TLR4 34 . In this study, we found that TiO 2 NPs cause an increase in the expression of TLR gene and in the levels of the related protein in immune cells of Paracentrotus lividus .…”

Recent Advances in Antibacterial and Antiendotoxic Peptides or Proteins from Marine Resources

“…A large amount of LPS is released from Gram-negative bacteria and forms micelles. Positively charged AMP and negatively charged LPS will move close to each other through electrostatic interactions [ 71 ]. AMPs may insert deeply into the interior of LPS micelles by hydrophobic interactions and finally can interact with the acyl chains of lipid A through specific amino acid side chains [ 72 ].…”

Patrones moleculares asociados a patógenos – ¿héroes o villanos en Nanomedicina?

“…Dentro de un animal, cualquier agente extraño, tal como una bacteria o una nanopartícula serán reconocidas como una sustancia extraña, y bastarán unos cuantos segundos para que tales agentes sean destruidos a través del sistema inmune (Sompayrac, 2012; Puntes y Saldaña, 2015). Más aún, las células encargadas de reconocer lo extraño podrían salirse de control, activarse de manera exacerbada y conducir a una respuesta inflamatoria capaz de acarrear efectos letales para el individuo (Peri et al, 2012). Debido a ello, con el diseño de nanopartículas se busca con frecuencia el camuflaje, es decir, el recubrimiento de partículas de tal manera que su paso por el organismo pueda permanecer inadvertido por parte del sis-tema inmune hasta llegar al blanco.…”