Polymorphisms of the toll-like receptor 2 and 4 genes are associated with faster progression and a more severe course of sepsis in critically ill patients

Nachtigall, Irit; Tamarkin, Andrey; Tafelski, Sascha; Weimann, Andreas; Rothbart, Andreas; Heim, Susanne; Wernecke, Klaus D.; Spies, Claudia

doi:10.1177/0300060513504358

Cited by 36 publications

(31 citation statements)

References 38 publications

(43 reference statements)

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“…TLR2 is expressed not only in immune cells, but is also present in pulmonary alveoli and airway epithelial cells, suggesting that it plays a role in mucosal innate immunity and infection-induced lung injury (Charles et al, 2011; Hertz et al, 2003; Hoth et al, 2012; Jiang et al, 2005). Interestingly, TLR2 deficient mice are highly susceptible to S. aureus infection (Takeuchi et al, 2000), and in humans, a loss-of-function TLR2 mutation has been linked to susceptibility to infectious and inflammatory diseases, faster disease progression, and a more severe course of sepsis in critically ill patients (Bronkhorst et al, 2013; Janardhanan et al, 2013; Nachtigall et al, 2014; Stappers et al, 2014). These studies illustrate the protective role of TLR2 in response to inflammatory insults and infectious diseases.…”

Section: Introductionmentioning

confidence: 99%

RING finger E3 ligase PPP1R11 regulates TLR2 signaling and innate immunity

McKelvey

Dunn

Evankovich

et al. 2016

eLife

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Toll-like receptor 2 (TLR2) is a pattern recognition receptor that recognizes many types of PAMPs that originate from gram-positive bacteria. Here we describe a novel mechanism regulating TLR2 protein expression and subsequent cytokine release through the ubiquitination and degradation of the receptor in response to ligand stimulation. We show a new mechanism in which an uncharacterized RING finger E3 ligase, PPP1R11, directly ubiquitinates TLR2 both in vitro and in vivo, which leads to TLR2 degradation and disruption of the signaling cascade. Lentiviral gene transfer or knockdown of PPP1R11 in mouse lungs significantly affects lung inflammation and the clearance of Staphylococcus aureus. There is a negative correlation between PPP1R11 and TLR2 levels in white blood cell samples isolated from patients with Staphylococcus aureus infections. These results suggest that PPP1R11 plays an important role in regulating innate immunity and gram-positive bacterial clearance by functioning, in part, through the ubiquitination and degradation of TLR2.DOI: http://dx.doi.org/10.7554/eLife.18496.001

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Section: Introductionmentioning

confidence: 99%

RING finger E3 ligase PPP1R11 regulates TLR2 signaling and innate immunity

McKelvey

Dunn

Evankovich

et al. 2016

eLife

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“…Therefore, some of the gene polymorphisms (GPs) influencing normal immune system function have been studied to analyze if giving prophylactic antibiotics to a group with susceptibility is more efficient. This has been done in cancer patients in a limited number of groups (Dahmer et al, 2005;Nachtigal et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Gene Polymorphisms and Febrile Neutropenia in Acute Leukemia—No Association with IL-4, CCR-5, IL-1RA, but the MBL-2, ACE, and TLR-4 Are Associated with the Disease in Turkish Patients: A Preliminary Study

Pehlıvan

Şahin

Özdilli

et al. 2014

Genetic Testing and Molecular Biomarkers

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“…In addition, a study by Nachtigall et al . reported that the polymorphism rs4986790 might shorten the time-to-onset of severe sepsis or septic shock in patients permitted to intensive care units45. In the study by Child et al ., the polymorphism rs4986790 was demonstrated to be involved in the severity of SIRS46.…”

Section: Discussionmentioning

confidence: 95%

The relationship between toll like receptor 4 gene rs4986790 and rs4986791 polymorphisms and sepsis susceptibility: A meta-analysis

Wang

et al. 2016

Sci Rep

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Accumulating evidences have demonstrated that lipopolysaccharide (LPS) represents the important etiologic factor for sepsis. Some previous studies have reported the relationship between common polymorphisms rs4986790 and rs4986791 in the coding gene for this receptor and the susceptibility to sepsis, but there were distinct divergences between those findings. We therefore designed this meta-analysis incorporated 28 published articles containing 6,537 sepsis patients and 8,832 controls for a more comprehensive conclusion on this matter. Odds ratios (ORs) and 95% confidence interval (95% CIs) were calculated to evaluate the association of toll like receptor 4 gene polymorphisms rs4986790 and rs4986791 with sepsis risk. Heterogeneity between included studies was inspected using Q test, and sensitivity analysis was implemented via sequential deletion of each included study to investigate the stability of overall estimates. Funnel plot and Egger’s test were adopted to examine publication bias across selected studies. We found no significant association for either the polymorphism rs4986790 or rs4986791 with sepsis susceptibility in total analysis under any genetic models. Neither did we after combining these two polymorphisms. 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.

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Polymorphisms of the toll-like receptor 2 and 4 genes are associated with faster progression and a more severe course of sepsis in critically ill patients

Abstract: Two common SNPs of the TLR2 and TLR4 genes--Arg753Gln and Asp299Gly--were associated with a shorter time-to-onset of severe sepsis or septic shock in patients admitted to the ICU.

Cited by 36 publications

References 38 publications

RING finger E3 ligase PPP1R11 regulates TLR2 signaling and innate immunity

RING finger E3 ligase PPP1R11 regulates TLR2 signaling and innate immunity

Gene Polymorphisms and Febrile Neutropenia in Acute Leukemia—No Association with IL-4, CCR-5, IL-1RA, but the MBL-2, ACE, and TLR-4 Are Associated with the Disease in Turkish Patients: A Preliminary Study

The relationship between toll like receptor 4 gene rs4986790 and rs4986791 polymorphisms and sepsis susceptibility: A meta-analysis

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