TLR4

Official Full Name

toll like receptor 4

Organism

Homo sapiens

GeneID

7099

Background

The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. In silico studies have found a particularly strong binding of surface TLR4 with the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease-2019 (COVID-19). This receptor has also been implicated in signal transduction events induced by lipopolysaccharide (LPS) found in most gram-negative bacteria. Mutations in this gene have been associated with differences in LPS responsiveness, and with susceptibility to age-related macular degeneration. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2020]

Synonyms

TOLL; CD284; TLR-4; ARMD10;

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Detailed Information

TLR4, also designated as CD284, is a germline-encoded transmembrane protein, and its molecular weight is approximately 95 kDa. TLR4 is a member of Toll-like receptor family which belongs to pattern-recognition receptors (PRR). TLR4 specifically recognizes bacterial lipopolysaccharide (LPS), along with several other components of pathogens and endogenous molecules produced during abnormal situations, such as tissue damage. Its activation leads to an intracellular signaling pathway NF-κβ and inflammatory cytokine production, thus initiating the innate immune response in mammalian animals. Cause the diversity of TLR4 gene, cellular expression patterns and tissue distribution, TLR4 functions vary across different species.

Overview of TLR4 Signaling Pathway

The TLR4 signaling pathway has been extensively studied. Briefly, when a ligand binds to the cell surface, the TLR4 receptor forms a homodimer through the interaction between its intracellular TIR-domains, resulting in a change in molecular conformation. Then the adapter molecules containing the TIR-domains are recruited to the cytoplasmic surface of the TLR4 cluster by homophilic interactions between the TIR-domains. Four adapter molecules containing the TIR-domains, belonging to two different pathways, are known for mediating TLR4 signaling: Myeloid Differentiation primary response gene 88 (MyD88), TIR Domain-Containing Adaptor Protein (TIRAP/Mal) and TIR-domain-containing adapter inducing interferon-β (TRIF/TICAM-1), TRIF-related adapter molecule (TRAM/TIRP/TICAM-2). The TIRAP–MyD88 pathway regulates early NF-kβ activation and related inflammatory cytokine production, such as IL-12. The TRIF–TRAM pathway activates IRF3 transcription factor, which effectuates the subsequent up-regulation of genes encoding type I interferons (IFNs) and co-stimulatory molecules, and TNF-α production and secretion, is also responsible for the late phase NF-kβ activation through IRF3 and TNF-a secretion.

Figure 1. TLR4 intracellular signaling pathways (Monica Molteni, 2018)

Pathologies Related to TLR4 Signaling

TLR4 and insulin resistance, DM

TLR4 does have a close relationship with insulin resistance. Chronic TLR4 activation may contribute to the insulin resistance. And FFAs act as an endogenous ligand (not directly) of TLR4 stimulating adipose tissue. TLR4 is closely related to inflammation, and insulin resistance in the early stages of chronic inflammation affects the development of diabetes. All these indicate that TLR4 has a certain correlation with DM.

TLR4 and AD

TLR4 is widely distributed in the brain and TLR4-dependent signaling pathway regulates neuroinflammation via activation of microglia. TLR4 can directly interact with Aβ to induce microglia Aβ phagocytosis in the early stage, but chronic long-term activation of TLR4 eventually lead to Aβ deposition.

TLR4 Antagonists and Clinical Application

The molecules extracted from plants, mediating TLR4 activation or inhibitory, promote the study of the molecular mechanisms of TLR4 modulators. And some synthetic TLR4 antagonists are already in clinical trials, promising to treat major human diseases.

Table 1. Results of the phase II and III clinical trials for TLR4-antagonists (Nikolay N. Kuzmich, 2017)

Substance name	Mechanism of action	Clinical trial, design and results
TAK-242 (Resatorvid)	Binds to Cys747 of TLR4-TIR domain, blocks TLR4/TIRAP and TLR4/TRAM interactions	Randomized, double-blind, placebo-controlled phase 2 trial (274 patients). Failed to suppress cytokine levels in patients with sepsis and shock or respiratory failure.
Eritoran (E5564)	Lipid A mimic, binds to MD-2	Phase 2, double-blind, placebo-controlled, ascending-dose study (152 patients). Eritoran was well tolerated but did not attenuated systemic inflammation significantly Randomized, double-blind, placebo-controlled, multinational phase 3 trial (1961 patient). Treatment did not improve 28-day survival.

References:

Liu CVaY. A comparative review of toll-like receptor 4 expression and functionality in different animal species. Frontiers in Immunology. 2014; 316.
G.S. Hotamisligil NSS, B.M. Spiegelman. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259: 87-91.
M. Song JJ. et al. TLR4 mutation reduces microglial activation, increases A beta deposits and exacerbates cognitive deficits in a mouse model of Alzheimer’s disease. J Neuroinflammation. 2011;8.
M.E. Gambuzza VS. et al. Toll-like receptors in Alzheimer’s disease: a therapeutic perspective. CNS Neurol Disord Drug Targets. 2014;13:1542-58.
E.G. Reed-Geaghan JCS, et al. CD14 and toll-like receptors 2 and 4 are required for fibrillar Aβ-stimulated microglial activation. J Neurosci. 2009;29 (38): 11982-92.
Nikolay N. Kuzmich. et al. TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis. Vaccines. 2017, 5, 34.

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