The results of this meta-analysis suggest that the rs4986790 and rs4986791 polymorphisms in toll like receptor 4 gene may have no statistically significant influence on sepsis susceptibility.
Candidate single nucleotide polymorphisms (SNPs) within bacterial recognition (TLR4 +896, CD14 -159) and inflammatory response (TNF-alpha -308, IL-1beta -31, IL-6 -174) loci were evaluated for association with increased risk for severe sepsis (sepsis plus organ dysfunction or septic shock) and mortality.
Adjusting for independent risk factors, carriage of the variant TLR4 896 G allele was associated with decreased risk of complicated sepsis (odds ratio = 0.3, 95% confidence interval, 0.1-0.7, p = 0.008).
The toll-like receptor 4/2242 polymorphism is a functional variant and might be used as a relevant risk estimate for organ dysfunction and sepsis in trauma patients.
Candidate genes for asthma and allergic diseases co-associated with sepsis including innate immunity receptors and related molecules (CD14, TLR4 and AOAH) and novel genes such as MYLK provide good examples of pleitropic effects of innate immunity genes, where variants conferring risk to specific traits (i.e. sepsis) under one set of genetic and environmental circumstances confer a reduced risk in a different (but possibly related) clinical outcome (i.e. allergic asthma), and support the 'common variant/multiple disease' hypothesis.
Our study investigated the association between TLR4 mutations (Asp299Gly and Thr399Ile) and CD14 polymorphism(s) with outcome in an intensive care unit (ICU) population at risk for sepsis.
Influence of genetic variations in TLR4 and TIRAP/Mal on the course of sepsis and pneumonia and cytokine release: an observational study in three cohorts.
Examples include variants of TLR4 in sepsis, malaria, inflammatory bowel disease and atherosclerosis; variants in TLR2 in tuberculosis and asthma; a variant in Mal (a key signal for TLR2 and TLR4) in malaria, tuberculosis and systemic lupus erythematosus; and variants in the kinase IRAK4 in pyogenic infections.
Two commonly occurring SNPs in the human TLR4 gene (Asp299Gly and Thr399Ile) have been shown to be associated with increased risk of Gram-negative bacteremia in sepsis patients and with susceptibility to inflammatory bowel disease.
Serum levels of tumour necrosis factor, interleukin (IL)-10, and IL-6 at sepsis onset did not significantly differ between patients carrying wild-type and mutant TLR4.
In conclusion, differences in distribution of TLR4 polymorphisms Asp299Gly and Thr399Ile in European populations are most likely due to a combination of population migration events combined with selection due to sepsis.
Specific point mutations in the human toll-like receptor 4 (TLR4) confer altered risk for diverse diseases including sepsis, aspergillosis and inflammatory bowel disease.
Combined with our previous in vitro functional study, the results suggest that the TLR4 11367 polymorphism might be a good predictor of who is more likely to develop complications such as sepsis or multiple organ dysfunction syndrome, depending on genotype.
Furthermore, the cosegregating TLR4 polymorphisms Asp299Gly and Thr399Ile were independent risk factors for the development of both sepsis and pneumonia (OR: 3.55; 95% CI: 1.21-10.4, P=0.021 and OR: 3.57, 95% CI: 1.3-9.86, P=0.014, respectively).
Some, but not all, epidemiological studies have suggested that Toll-like receptor 4 (TLR4) polymorphisms, Asp299Gly and Thr399Ile, may influence the risk of at-risk patients for sepsis.
The rs11536889 polymorphism in TLR4 and rs2563298 polymorphism in CD14 were significantly associated with the risk of sepsis when compared to the control group.
During hemorrhagic shock and sepsis, inflammation triggers the translocation of CIRP from the nucleus to the cytosol and its release to the extracellular space. eCIRP then induces inflammatory responses in macrophages, neutrophils, lymphocytes, and dendritic cells. eCIRP also induces endoplasmic reticulum stress and pyroptosis in endothelial cells by activating the NF-κB and inflammasome pathways, and necroptosis in macrophages via mitochondrial DNA damage. eCIRP works through the TLR4-MD2 receptors.
Our results indicate that TFAM repairs mtDNA by blocking the TLR4/ROS/P38MAPK signaling pathway in inflammatory cells, thereby repairing septic tubular epithelial cells, and TFAM may serve as a new target for sepsis therapy.
Toll-like receptor 4 (TLR4)-a transmembrane pattern-recognition receptor responsible for propagating the immediate immune response to Gram-negative bacterial infection-plays a central role in the pathogenesis of sepsis and chronic inflammation-related disorders.
Collectively, the results from the current study demonstrate CD16 as a key regulator of the TRIF-dependent TLR4 pathway in human monocytes and their CD16-expressing subset, with implications in sepsis.
Hyporesponsiveness by phagocytes is a well-known phenomenon in sepsis that is frequently induced by low-dose endotoxin stimulation of Toll-like receptor 4 (TLR4) but can also be found under sterile inflammatory conditions.