Toll-Like Receptors
Toll-like receptors featured article
Toll-like receptors are a family of pattern recognition receptors expressed on the surface of immune and other cells. Toll-like receptors are the principal inducers of innate immunity, activating transcription factors such as NF-kB that increase the expression of inflammatory cytokines. Among toll-like receptors, TLR4 is notable for recognizing lipopolysaccharide (LPS), a structure found on the outer membranes of Gram-negative bacteria. This overview will predominantly focus on TLR4 and its involvement in human health, disease, and behavior.
Toll-like receptors are a gateway to understanding how innate immunity influences aging.
While the innate inflammatory response is necessary for immunity against bacterial infection, chronic activation of the TLR4 pathway can accelerate aspects of aging, a phenomenon termed inflammaging. One source of TLR4-mediated innate immune activation is thought to be chronic exposure to lipopolysaccharide by certain...
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Toll-like receptors
Toll-like receptors are transmembrane pattern-recognition receptors that, via MyD88 or TRIF pathways, activate NF-κB–mediated inflammatory transcription.
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Curcumin may act as an intervention in chronic urinary tract infection through dampening of toll-like receptors and reducing bacterial colony count pubmed.ncbi.nlm.nih.gov
Curcumin reduces urinary tract infection symptoms via interaction with toll-like receptors.
Urinary tract infections are common outpatient infections. They occur more frequently among women, and 50 to 60 percent of all women report having had at least one UTI in their lifetime. Findings from a 2017 study suggest that curcumin reduces the symptoms associated with urinary tract infections via interaction with toll-like receptors.
Toll-like receptors comprise a family of pattern recognition receptors expressed on the surfaces of immune and other cells. They are the principal inducers of innate immunity and are responsible for the activation of transcription factors that increase the expression of proinflammatory cytokines. Chronic infections of the urinary tract, which either don’t respond to treatment or keep recurring, can occur in some people.
Curcumin is a bioactive compound found in the roots of Curcuma longa, a type of tropical plant. It is responsible for the vibrant yellow color of the spice turmeric. Evidence suggests that curcumin exerts robust antioxidant, anti-inflammatory, and anticancer effects. Curcumin also exhibits antibacterial activity, but the compound is strain-specific.
The study involved rats that had chronic urinary tract infections. Half of the rats received a curcumin injection, while the other half did not. The investigators measured the animals' white blood cell counts, bacterial counts (in the bladder and urine), markers of inflammation, and expression of toll-like receptor (TLR)2 and TLR4.
They found that white blood cell counts, bacterial counts, markers of inflammation, and expression of TLR2 and TLR4 of the rats that received the curcumin injection were considerably lower than those of the rats that didn’t receive curcumin. These findings suggest that curcumin improves the symptoms of chronic urinary tract infections and reduces inflammatory responses via dampening the expression of TLR2 and TLR4.
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Chronic systemic inflammation induced by lipopolysaccharide can cause microglia to attack the blood-brain barrier www.sciencedaily.com
Obesity promotes circulation of lipopolysaccharide. In animals, chronic systemic inflammation, experimentally induced by injection with LPS, also known as “LPS challenge,” can cause microglia into the brain to switch from protecting the blood-brain barrier to damaging it.
From the article:
Nearly 50 percent of all dementias, including Alzheimer’s, begins with the breakdown of the smallest blood vessels in the brain and their protective “gatekeeper cells,” according to a Keck School of Medicine of USC study.
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A key point of interest was the systemic inflammation induced by injecting the mice with an inflammation-inducing substance. Such injections resulted in the movement of microglia to the blood vessels and increased the permeability of the blood-brain barrier within a few days. Then, the microglia initially acted to protect the blood-brain barrier and limit increases in permeability, but as inflammation progressed, the microglia reversed their behavior by attacking the components of the blood-brain barrier, thus increasing the barrier’s permeability. The subsequent leakage of molecules into the brain had the potential to cause widespread inflammation in the brain and consequent damage to neurons (cells of the nerves).
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Inflammatory injury from obesity is mediated by activation of TLR4 (but may be ameliorated by omega-3) www.sciencedaily.com
Knocking out TLR4 in mice ameliorates obesity-associated inflammation, which may come as no surprise since increased circulation of LPS (a potent activator of TLR4) has been implicated in obesity due to associations with increased presence of LPS binding protein.
While genetically knocking out TLR4 is probably not a practical solution to the inflammatory cascade associated with human obesity, which may also be a smoking gun in obesity-associated brain shrinkage and diminished cognition, dietary intake of omega-3 fatty acids EPA and DHA may at least be partly ameliorative (see review). Additionally, a study in breast cancer patients showed that 5 grams per day of EPA and DHA ultimately lead to hypermethylation (usually interpreted as suppressive) of TLR4.
From the article:
When a person consumes more calories than needed, the excess calories are stored in the form of triglycerides inside fat tissue, also known as white adipose tissue (WAT). Researchers know that in obese people, WAT becomes overworked, fat cells begin to die, and immune cells become activated. But the exact mechanism by which this inflammation occurs isn’t fully understood.
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After five months on a high-fat diet, the mice lacking Tlr4 had gained just as much weight, and just as much fat, as other mice on a high-fat diet. But the genetically engineered mice – with [fibro-inflammatory progenitors] that could no longer generate the same signals – no longer had high levels of inflammation. Instead, the levels of inflammatory molecules in their WAT were closer to the levels seen in mice on low-fat diets.
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Suppression of TLR4 gene shown in animals to protect against retinal cell death associated with acute glaucoma www.sciencedaily.com
From the article:
In the study, researchers showed that a rapid, sustained large increase in eye pressure in mice turns on a gene (TLR4) that activates a protein known as caspase-8. This signaling protein in turn triggers the production of inflammatory proteins that normally help mammals fight microbial infections.
“This immune response is a double-edge sword because, while these proteins protect us from infection in a normal situation, they stimulate apoptosis (programmed cell death) in retinal cells in cases of acute glaucoma,” said Zhang, who is also a staff physician at the Veterans Affairs San Diego Healthcare System.
To further confirm the mechanism linking high eye pressure to retinal damage, researchers showed that they could slow retinal cell death in mice with acute glaucoma by suppressing either the TLR4 gene or caspace-8 protein.
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Animal research suggests fragmented sleep promotes cancer through increases in TLR4 which polarize macrophages towards immune suppressive M2 type www.sciencedaily.com
Poor sleep drives cancer growth by decreasing a type of immune cell that eliminates tumors.
Scientists have long known that people who don’t get enough sleep are at greater risk of developing cancer. Once a person develops cancer, how long and how well they sleep can influence their disease outcome. A 2014 study implicated tumor-associated macrophages and toll-like receptor (TLR)- 4 as the primary drivers of unfavorable cancer outcomes in the setting of poor sleep.
Tumor-associated macrophages are white blood cells that play important roles in cancer progression. M1 macrophages, which have a proinflammatory phenotype, can eliminate cancer cells. M2 macrophages, which have an anti-inflammatory phenotype, suppress immune activity and promote blood vessel growth – a critical aspect of tumor survival.
TLR-4 is a receptor protein found on the surface of immune and other cells. TLR-4 activates transcription factors that promote the expression of pro-inflammatory cytokines. While this inflammatory response is necessary for immunity against bacterial infection, chronic activation of the TLR-4 pathway can accelerate aging and increase the risk for many diseases, including cancer.
The investigators interrupted the sleep of normal mice and mice that lacked TLR-4, mimicking the effects of several sleep disorders. After the mice developed cancer, the investigators noted characteristics of the animals' tumors, including size, invasiveness, and the type and number of tumor-associated macrophages.
They found that the mice that experience interrupted sleep had larger, more invasive tumors and larger numbers of tumor-associated macrophages than the mice that had uninterrupted sleep. However, these effects were not observed in the mice that lacked TLR4.
These findings suggest that poor, fragmented sleep promotes tumor growth and invasiveness via activation of TLR4 pathways and subsequent recruitment of tumor-associated macrophages. Learn more about the varied roles TLR4 plays in human health in our overview article.
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TLR4 exacerbates necrotizing enterocolitis, a leading cause of death in premature newborns, by stopping enterocytes from closing wounds in intestines www.sciencedaily.com
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Blocking signals from a key molecular receptor that normally switches on the intestine’s immune response but instead becomes too intense in the presence of stress and toxins may help reverse necrotizing enterocolitis (NEC), a leading cause of death in premature newborns.
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But Hackam’s group found that the stresses of oxygen deprivation and bombardment by bacterial toxins, conditions that can occur in premature infants with underdeveloped lungs, stimulate too much production of TLR4. Like an unstoppable alarm, the increased numbers of TLR4 blare out signals that eventually tip the cells into cellular suicide. They also stop enterocytes from migrating to close wounds in the intestines.
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Silencing TLR4 gene can stop process leading to cardiovascular disease in diabetics (animal study) www.sciencedaily.com
TLR4 plays a role in death of heart cells from high blood sugar.
From the article:
Researchers writing in BioMed Central’s open access Journal of Translational Medicine carried out a series of in vitro tests which demonstrated that TLR4 plays a critical role in hyperglycaemic cardiac apoptosis, and that silencing the gene using specific small interfering RNA (siRNA) can prevent it.
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They found that after 7 days of hyperglycemia, the level of TLR4 mRNA in myocardial tissue was significantly elevated, and signs of apoptosis were evident. Silencing TLR4 resulted in suppression of apoptotic cascades. According to Min, “This is the first demonstration of the prevention of cardiac apoptosis in diabetic mice through silencing of the TLR4 gene.”
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Blocking toll-like receptor 4 with Naltrexone reduces alcohol seeking behavior in mice www.sciencedaily.com
The circadian rhythm aspect of drug rewards: “Our body’s circadian rhythms affect the ‘reward’ signals we receive in the brain from drug-related behavior, and the peak time for this reward typically occurs during the evening, or dark phase. We wanted to test what the role of the brain’s immune system might have on that reward, and whether or not we could switch it off.”
Using naltrexone to block TLR4 reduces alcohol behavior:
The researchers focused their attention on the immune receptor Toll-like receptor 4 (TLR4). They administered the drug (+)-Naltrexone (pronounced: PLUS-NAL-TREX-OWN), which is known to block TLR4, to mice.
“Our studies showed a significant reduction in alcohol drinking behavior by mice that had been given (+)-Naltrexone, specifically at night time when the reward for drug-related behavior is usually at its greatest,” Mr Jacobsen says.
Interestingly and somewhat paradoxically, chronically activating TLR4 through genetic engineering-associated tricks also seems to reduce alcohol seeking in mice.
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Cellular stress with changes in microbial profile promotes colorectal cancer development www.sciencedaily.com
Activation of ATF6, a regulator of ER (Endoplasmatic Reticulum) stress, combined with changes in cecal microbial profile, promoted colon adenoma formation.
[Abstract]
Methods: We analyzed data from 541 patients with CRC in the TCGA database for genetic variants and aberrant expression levels of unfolded protein response genes. Findings were validated in a cohort of 83 patients with CRC in Germany. We generated mice with intestinal epithelial cell-specific expression of the active form of ATF6 (nATF6IEC) from 2 alleles (homozygous), mice with expression of nATF6IEC from 1 allele (heterozygous), and nATF6IECfl/fl mice (controls). All nATF6IEC mice were housed under either specific-pathogen free or germ-free conditions. Cecal microbiota from homozygous nATF6IEC mice or control mice was transferred into homozygous nATF6IEC mice or control mice. nATF6IEC mice were crossed with mice with disruptions in the myeloid differentiation primary response gene 88 and toll-like receptor adaptor molecule 1 gene (Myd88/TRIF knock-out mice). Intestinal tissues were collected from mice and analyzed by histology, immunohistochemistry, immunoblots, gene expression profiling of unfolded protein response and inflammatory genes, array-based comparative genome hybridization, and 16S rRNA gene sequencing.
Results: Increased expression of ATF6 was associated with reduced disease-free survival times of patients with CRC. Homozygous nATF6IEC mice developed spontaneous colon adenomas at 12 weeks of age. Compared to controls, homozygous nATF6IEC mice had changes in the profile of their cecal microbiota, increased proliferation of intestinal epithelial cells, and loss of the mucus barrier—all preceding tumor formation. These mice had increased penetration of bacteria into the inner mucus layer and activation of STAT3, yet inflammation was not observed at the pre-tumor or tumor stages. Administration of antibiotics to homozygous nATF6IEC mice greatly reduced tumor incidence, and germ-free housing completely prevented tumorigenesis. Analysis of nATF6IEC MyD88/TRIF knock-out mice showed that tumor initiation and growth required MyD88/TRIF-dependent activation of STAT3. Transplantation of cecal microbiota from nATF6IEC mice and control mice, collected before tumor formation, caused tumor formation in ex–germ-free nATF6IEC mice.
Conclusions: In patients with CRC, ATF6 was associated with reduced time of disease-free survival. In studies of nATF6IEC mice, we found sustained intestinal activation of ATF6 in the colon to promote dysbiosis and microbiota-dependent tumorigenesis.