4G8A, 2Z62, 2Z63, 2Z65, 2Z66, 3FXI, 3UL7, 3UL8, 3UL9, 3ULA709921898ENSG00000136869ENSMUSG00000039005O00206Q9QUK6NM_138557NM_003266NM_138554NM_138556NM_021297NP_003257NP_612564NP_612567NP_067272Toll-like receptor 4 (TLR4), also designated as CD284 (cluster of differentiation 284), is a key activator of the innate immune response and plays a central role in the fight against bacterial infections.
The recognition of a PAMP by a PRR triggers rapid activation of the innate immunity essential to fight infectious diseases.
Most myeloid cells express also high amounts of plasma membrane-anchored CD14, which facilitates the activation of TLR4 by LPS and controls the subsequent internalization of the LPS-activated TLR4 important for receptor signaling and degradation.
During infection, TLR4 responds to the LPS present in tissues and the bloodstream and triggers pro-inflammatory reactions facilitating eradication of the invading bacteria.
[13] TLR4 is also involved in the recognition of endogenous DAMP molecules leading to different signaling outcomes than PAMPs, both quantitatively and qualitatively.
However, in some cases, an excessive and/or poorly regulated inflammatory response to DAMPs can be detrimental to the organism, accelerating the development or progression of pathologies such as a number of cancers and neurodegenerative diseases (as discussed below).
LPS stimulation induces a series of interactions with several accessory proteins which form the TLR4 complex on the cell surface.
The conformational changes of the TLR4 induce the recruitment of intracellular adaptor proteins containing the TIR domain which is necessary to activate the downstream signaling pathway.
[22][23] The molecular structure of TLR4 ligands (in particular LPS), as well as their complexation with proteins or lipids, greatly influence the action of these TLR4-related signaling pathways, leading to different cytokine balances.
[28][29] These two transcription factorsnduces the expression of genes encoding pro-inflammatory mediators, such as tumor necrosis factor α (TNF-α), interleukin (IL)-6, and type III interferons (IFNλ1/2).
[35] TLR4 activation by LPS enables a rapid stimulation of a whide range of innate immune cells such as macrophages and DCs.
[36][37] This explains why TLR4 activation by LPS is also known to stimulate the generation of effective adaptive immune responses and to induce their recruitment, polarization and maintenance via the panel of cytokines and chemokines produced.
[46] The activation of MyD88 and TRIF signaling pathways were also found to induce Th1 polarization of the T cells responses through DC maturation and the panel of cytokines produced.
[47][48][49] Low activation of MYD88 pathway is however important for effective cytotoxic T-cell differentiation by facilitating fusion of MHC I-bearing recycling endosomes with phagosomes allowing cross-presentation of antigens.
The impact of TLR4 activation on the innate and adaptive immune system explains why TLR4 agonists, such as LPS derivatives, have been developed as vaccine adjuvants.
For some of them, an association with increased susceptibility to Gram-negative bacterial infections or faster progression and a more severe course of sepsis in critically ill patients was reported.However, they are very rare, and their frequency varies according to ethnic origin.
TLR4 play a central role in the control of bacterial infections through the recognition of LPS molecules from gram-negative, and some gram-positive, bacteria.
[67] Since then, a number of developments have been made in the treatment or prevention of cancer using bacterial mixtures strongly activating TLR4 due to LPS content.
The antituberculosis vaccine Bacillus Calmette–Guérin (BCG) was approved by the Federal Drug Administration (FDA) in 1990 for the local treatment of superficial bladder cancer.
[68] There are also reports on the treatment of oral squamous cell carcinoma, gastric , Head-and-neck and cervical cancers with lyophilized streptococcal preparation OK-432 (Picibanil).
[71][72] In the 90’s, clinical trials evaluating the intravenous administration of LPS to patients with cancer provided positive results including several cases of disease stabilization and partial responses.
This includes the MPL, a chemically modified LPS which was the first TLR4 agonist to be approved and commercialized by GSK in 5 human vaccines (HPV, Zoster, Hepatitis B, Malaria, RSV).
MPL was investigated as an adjuvant for curative anti-tumor vaccines, with the approval of Melacine in Canada for the treatment of patients with malignant melanoma.
[74] Synthetic LPS derivatives based on dephosphorylated lipid A moiety structures were also developed and confirmed potent adjuvant and antitumor activities as therapeutic agents.
In particular, the intratumoral administration of Glucopyranosyl Lipid Adjuvant (GLA-SE/G100), a synthetic detoxified analog of lipid A formulated in a stable emulsion, showed anti-tumor immune responses and tumor regression in patients with Merkel cell carcinoma,[75] and potent adjuvant activity in phase 2 trials in combination with pembrolizumab in patients with follicular lymphoma.
On the contrary, in phase 2 studies with GLA, a positive association between baseline TLR4 expression in tumors and the increase of overall response rates has been reported.
[85] However, chronic TLR4 activation is believed to be associated with glia-mediated neuronal death due to excessive secretion of pro-inflammatory cytotoxins leading to neuroinflammation, a key factor in the development of many neurodegenerative diseases.
[88] All these structures bind TLR4 and activate downstream signaling pathways in glia, inducing secretion of reactive oxygen species (ROS) and proinflammatory cytokines such as IL-1β and TNF-α, which can lead to damage and death of neurons.
[96] Some studies showed that selective TLR4 agonists could be beneficial by upregulating the phagocytic activity of microglia, leading to enhanced clearance of damaged tissue and abnormal protein aggregates associated with several different CNS diseases.