Single-nucleotide polymorphisms in the Toll-like receptor pathway increase susceptibility to infections in severely injured trauma patients

Bronkhorst, M.W.G.A.; Boyé, N.D.A.; Lomax, M.A.Z.; Vossen, Rolf H. A. M.; Bakker, Jan; Lieshout, Esther M.M. Van

doi:10.1097/ta.0b013e31827e1534

Cited by 30 publications

(26 citation statements)

References 39 publications

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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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“…The factors that determine these changes are not known but expression levels do appear to correlate with susceptibility to Gram-positive sepsis post-trauma (19). Furthermore, certain polymorphisms in the TLR2 gene correlate with susceptibility to Gram-positive infections post-injury (21, 22). Although the key polymorphism (TLR2 T-16934ATA) correlates with ex vivo monocyte responses to TLR2 agonist, the presence of the polymorphism was not assessed for impact on circulating SIRS biomarkers in the patients.…”

Section: Discussionmentioning

confidence: 99%

“…Studies in human trauma show that surface expression of TLR2 on monocytes can either be up- or down-regulated early in the clinical course and that suppression of TLR2 expression is associated with an increased incidence of Gram-positive sepsis (19, 20). In addition, polymorphisms in the human TLR gene correlate with sepsis propensity following trauma in humans (21, 22). Taken together, these results would suggest that TLR2 expression is rapidly modified during H/R and that, while it plays a key role in microbial recognition after trauma, its role in the initiation of inflammatory pathways during H/R remains unresolved.…”

Section: Introductionmentioning

confidence: 99%

Tlr2 on Bone Marrow and Non-Bone Marrow Derived Cells Regulates Inflammation and Organ Injury in Cooperation with Tlr4 During Resuscitated Hemorrhagic Shock

Korff

Loughran

Cai

et al. 2016

Shock

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Background Although the role of TLR4 in driving inflammation and organ injury after hemorrhagic shock and resuscitation (H/R) is well established, the role of TLR2 - another receptor for damage-associated molecular pattern (DAMP) molecules - is not. In this study, we used a combination of TLR2−/− and wild type (WT) mice treated with anti-TLR2 and anti-TLR4 neutralizing monoclonal antibodies (mAb) to discern the contribution of TLR2 relative to TLR4 to the systemic inflammatory response in murine H/R. Material and Methods WT mice, TLR2−/− and WT mice receiving an anti-TLR2 or an anti-TLR4 mAB (given as a pre-treatment) were sacrificed at 6 or 20 hr post-H/R. Bone marrow TLR2/WT chimeric mice were created to assess the importance of immune and non-immune cell-associated TLR2. Results TLR2−/− mice subjected to H/R exhibited significantly less liver damage and lower markers of systemic inflammation only at 20 hr. Bone marrow chimeric mice using combinations of TLR2−/− mice and WT mice demonstrated that TLR2 on non-bone marrow derived cells played a dominant role in the differences at 20 hr. Interestingly, WT mice treated with anti-TLR2 mAB demonstrated a reduction in organ damage and systemic inflammation at both 6 and 20 hrs following H/R. A combination of anti-TLR2 mAB and anti-TLR4 mAB showed that both receptors drive IP-10 and KC levels and that there is cooperation for increases in IL-6, MIG, and MCP-1 levels between TLR2 and TLR4. Conclusion These data also support the conclusion that TLR2 and TLR4 act in concert as important receptors in the host immune response to H/R.

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“…TLR is another contributor in inflammatory immune responses during trauma-induced infections [43]. Aberrant activation of the TLR/CD14 pathway is related to the risk of infectious complications in severely injured trauma patients [44]. Genetic variation in TLR1 is also associated with increased mortality in patients with sepsis after traumatic injury.…”

Section: Discussionmentioning

confidence: 99%

Identification of a miRNA signature in neutrophils after traumatic injury

Yang¹,

Liang²,

Han³

et al. 2013

ABBS

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Traumatic injury is the cause of significant mortality and morbidity. The molecular mechanisms underlying traumatic injury logically involve changes in gene expression that may be regulated through microRNAs (miRNAs). However, the association between miRNA deregulation and traumatic injury is largely unknown. The purpose of the present study is to address this issue. In this study, we used microarray profiling to evaluate the differential expressions of miRNAs in neutrophils obtained from patients with major trauma (injury severity scores >16), relative to healthy individuals. This neutrophilic miRNA signature was further validated using quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). Genes and signaling pathways related to trauma-induced deregulated miRNAs were investigated in silico using the ontology-based and network mapping algorithms of Gene Ontology and Kyoto Encyclopedia of Genes or Genomes. Results showed that 13 miRNAs in neutrophils of major trauma patients were significantly and differentially expressed compared with the miRNA profiles of healthy controls. The results of qRT-PCR and in silico analysis revealed that miR-23a-5p, miR-30e-3p, miR-223-5p, miR-3945, miR-155-5p, and miR-150-5p were likely participants in the traumatic pathogenesis of these patients. In conclusion, neutrophils associated with traumatic injury were found to have a unique miRNA signature. Changes in signaling pathways due to deregulated miRNAs may be involved in the pathological processes of traumatic injury.

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Single-nucleotide polymorphisms in the Toll-like receptor pathway increase susceptibility to infections in severely injured trauma patients

Abstract: Background. Sepsis and subsequent multiple organ failure are the predominant causes of late

Cited by 30 publications

References 39 publications

RING finger E3 ligase PPP1R11 regulates TLR2 signaling and innate immunity

RING finger E3 ligase PPP1R11 regulates TLR2 signaling and innate immunity

Tlr2 on Bone Marrow and Non-Bone Marrow Derived Cells Regulates Inflammation and Organ Injury in Cooperation with Tlr4 During Resuscitated Hemorrhagic Shock

Identification of a miRNA signature in neutrophils after traumatic injury

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