Toll-like receptor 4 deficiency: Smaller infarcts, but nogain in function

<p>Abstract</p> <p>Backgound</p> <p>It has been reported that Toll-like receptor 4 (TLR4) deficiency reduces infarct size after myocardial ischemia/reperfusion (MI/R). However, measurement of MI/R injury was limited and did not include cardiac <b>function</b>. In a chronic closed-chest model we assessed whether cardiac <b>function </b>is preserved in TLR4-deficient mice (C3H/HeJ) following MI/R, and whether myocardial and systemic cytokine expression differed compared to wild type (WT).</p> <p>Results</p> <p>Infarct size (IS) in C3H/HeJ assessed by TTC staining after 60 min ischemia and 24h reperfusion was significantly smaller than in WT. Despite a smaller infarct size, echocardiography showed no functional difference between C3H/HeJ and WT. Left-ventricular developed pressure measured with a left-ventricular catheter was lower in C3H/HeJ (63.0 ± 4.2 mmHg vs. 77.9 ± 1.7 mmHg in WT, p < 0.05). Serum cytokine levels and myocardial IL-6 were higher in WT than in C3H/HeJ (p < 0.05). C3H/HeJ MI/R showed increased myocardial IL-1β and IL-6 expression compared to their respective shams (p < 0.05), indicating TLR4-independent cytokine activation due to MI/R.</p> <p>Conclusion</p> <p>These results demonstrate that, although a mutant TLR4 signaling cascade reduces myocardial IS and serum cytokine levels, it <b>does not preserve myocardial function</b>. The change in inflammatory response, secondary to a non-functional TLR-4 receptor, may contribute to the observed dichotomy between infarct size and function in the TLR-4 mutant mouse.</p

A stop codon polymorphism of toll-like receptor 5 is associated with a stable course of chronic obstructive lung disease

The etiology of chronic obstructive lung disease (COPD) is unclear. It is supposed to be the product of an exogenous antigenic stimulus, such as tobacco smoke, and an endogenous genetic susceptibility. Toll-like receptors (TLR) are signal molecules, essential for the cellular response to bacterial cell wall components. Lipopolysaccharide (LPS) binds to TLR4 and two different polymorphisms for the TLR4 gene (Asp299Gly and Thr399Ile) have recently been described. TLR5 is the receptor for flagellin, aconstituent of Gram-positive and -negative bacterial flagella. A functional relevant TLR5 polymorphism (TLR5392STOP) has already been identified. The coactivation of both TLR4 and 5 seems to play an important role in the mediation of host-defense mechanisms. We genotyped 138 Caucasian patients with COPD and 135 healthy controls for the TLR5 polymorphism TLR5392STOP respectively for Asp299Gly and Thr399Ile polymorphisms in theTLR4gene. Among COPD patients the prevalence for the TLR5 mutant allele was 9.42% (26/276). The prevalence for each Asp299Gly and Thr399Ile mutant allele was 4.71% (13/276). In the control group the TLR5 mutation prevalence was 5.19% (14/270) (P = 0.138), the prevalence of each TLR4 polymorphism was 2.96% (8/270) (p = 0.279). In the subgroup of 54 patients with a stable course of COPD, defined as less than three hospitalizations over the last three years due to COPD, we found a significant association with the TLR5392STOP gene polymorphism (P = 0.026). These data suggest that the TLR5392STOP polymorphism is associated with a stable course of COPD, whereas TLR4 polymorphisms have no impact neither on the onset nor on the course of COPD

Vascular dysfunction following polymicrobial sepsis: role of pattern recognition receptors.

AIMS: Aim was to elucidate the specific role of pattern recognition receptors in vascular dysfunction during polymicrobial sepsis (colon ascendens stent peritonitis, CASP). METHODS AND RESULTS: Vascular contractility of C57BL/6 (wildtype) mice and mice deficient for Toll-like receptor 2/4/9 (TLR2-D, TLR4-D, TLR9-D) or CD14 (CD14-D) was measured 18 h following CASP. mRNA expression of pro- (Tumor Necrosis Factor-α (TNFα), Interleukin (IL)-1β, IL-6) and anti-inflammatory cytokines (IL-10) and of vascular inducible NO-Synthase (iNOS) was determined using RT-qPCR. Wildtype mice exhibited a significant loss of vascular contractility after CASP. This was aggravated in TLR2-D mice, blunted in TLR4-D animals and abolished in TLR9-D and CD14-D animals. TNF-α expression was significantly up-regulated after CASP in wildtype and TLR2-D animals, but not in mice deficient for TLR4, -9 or CD14. iNOS was significantly up-regulated in TLR2-D animals only. TLR2-D animals showed significantly higher levels of TLR4, -9 and CD14. Application of H154-ODN, a TLR9 antagonist, attenuated CASP-induced cytokine release and vascular dysfunction in wildtype mice. CONCLUSIONS: Within our model, CD14 and TLR9 play a decisive role for the development of vascular dysfunction and thus can be effectively antagonized using H154-ODN. TLR2-D animals are more prone to polymicrobial sepsis, presumably due to up-regulation of TLR4, 9 and CD14

Toll-like receptor 4 deficiency: smaller infarcts, but no gain in function.

BackgroundIt has been reported that Toll-like receptor 4 (TLR4) deficiency reduces infarct size after myocardial ischemia/reperfusion (MI/R). However, measurement of MI/R injury was limited and did not include cardiac function. In a chronic closed-chest model we assessed whether cardiac function is preserved in TLR4-deficient mice (C3H/HeJ) following MI/R, and whether myocardial and systemic cytokine expression differed compared to wild type (WT).ResultsInfarct size (IS) in C3H/HeJ assessed by TTC staining after 60 min ischemia and 24h reperfusion was significantly smaller than in WT. Despite a smaller infarct size, echocardiography showed no functional difference between C3H/HeJ and WT. Left-ventricular developed pressure measured with a left-ventricular catheter was lower in C3H/HeJ (63.0 +/- 4.2 mmHg vs. 77.9 +/- 1.7 mmHg in WT, p &lt; 0.05). Serum cytokine levels and myocardial IL-6 were higher in WT than in C3H/HeJ (p &lt; 0.05). C3H/HeJ MI/R showed increased myocardial IL-1beta and IL-6 expression compared to their respective shams (p &lt; 0.05), indicating TLR4-independent cytokine activation due to MI/R.ConclusionThese results demonstrate that, although a mutant TLR4 signaling cascade reduces myocardial IS and serum cytokine levels, it does not preserve myocardial function. The change in inflammatory response, secondary to a non-functional TLR-4 receptor, may contribute to the observed dichotomy between infarct size and function in the TLR-4 mutant mouse

Toll-Like Receptor 9 Promotes Cardiac Inflammation and Heart Failure during Polymicrobial Sepsis

Background. Aim was to elucidate the role of toll-like receptor 9 (TLR9) in cardiac inflammation and septic heart failure in a murine model of polymicrobial sepsis. Methods. Sepsis was induced via colon ascendens stent peritonitis (CASP) in C57BL/6 wild-type (WT) and TLR9-deficient (TLR9-D) mice. Bacterial load in the peritoneal cavity and cardiac expression of inflammatory mediators were determined at 6, 12, 18, 24, and 36 h. Eighteen hours after CASP cardiac function was monitored in vivo. Sarcomere length of isolated cardiomyocytes was measured at 0.5 to 10 Hz after incubation with heat-inactivated bacteria. Results. CASP led to continuous release of bacteria into the peritoneal cavity, an increase of cytokines, and differential regulation of receptors of innate immunity in the heart. Eighteen hours after CASP WT mice developed septic heart failure characterised by reduction of end-systolic pressure, stroke volume, cardiac output, and parameters of contractility. This coincided with reduced cardiomyocyte sarcomere shortening. TLR9 deficiency resulted in significant reduction of cardiac inflammation and a sustained heart function. This was consistent with reduced mortality in TLR9-D compared to WT mice. Conclusions. In polymicrobial sepsis TLR9 signalling is pivotal to cardiac inflammation and septic heart failure