Selective NOD1 Agonists Cause Shock and Organ Injury/Dysfunction<i>In Vivo</i>

Cartwright, Neil; Murch, Oliver; McMaster, Shaun K.; Paul-Clark, Mark J.; Heel, David A. van; Ryffel, Bernhard; Quesniaux, Valérie; Evans, Timothy W.; Thiemermann, Christoph; Mitchell, Jane A.

doi:10.1164/rccm.200608-1103oc

Cited by 55 publications

(56 citation statements)

References 35 publications

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“…However, data from our group suggest that the actions of NOD1 vary between cell types and, unlike those seen with LPS, the in vivo effects may be independent of leukocyte activation. Specifically, we have shown that while selective activation of NOD1 in macrophages has no apparent effect, in vascular cells NOD1 activation results in the profound induction of NOSII and shock in vivo (Cartwright et al 2007). NOD2 is thought to be important in the maintenance of a healthy gut barrier since individuals who carry a defective NOD2 because of a polymorphism have an increased risk of Crohn's disease (Murillo et al 2003, Abreu et al 2005 or other intestinal disorders presumably because the lack of NOD2 compromises gut barrier function to bacteria.…”

Section: Nod Receptorsmentioning

confidence: 96%

Critical role of toll-like receptors and nucleotide oligomerisation domain in the regulation of health and disease

Mitchell¹,

Paul-Clark²,

Clarke³

et al. 2007

Journal of Endocrinology

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118

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Pathogens are sensed by pattern recognition receptors (PRRs), which are germ line-encoded receptors, including transmembrane Toll-like receptors (TLRs) and cytosolic nucleotide oligomerisation domain (NOD) proteins, containing leucine-rich repeats (NLRs). Activation of PRRs by specific pathogen-associated molecular patterns (PAMPs) results in genomic responses in host cells involving activation transcription factors and the induction of genes. There are now at least 10 TLRs in humans and 13 in mice, and 2 NLRs (NOD1 and NOD2). TLR signalling is via interactions with adaptor proteins including MyD88 and tollreceptor associated activator of interferon (TRIF). NOD signalling is via the inflammasome and involves activation of Rip-like interactive clarp kinase (RICK). Bacterial lipopolysaccharide (LPS) from Gram-negative bacteria is the beststudied PAMP and is activated by or 'sensed' by TLR4. Lipoteichoic acid (LTA) from Gram-positive bacteria is sensed by TLR2. TLR4 and TLR2 have different signalling cascades, although activation of either results in symptoms of sepsis and shock. This review describes the rapidly expanding field of pathogen-sensing receptors and uses LPS and LTA as examples of how these pathways parallel and diverge from each other. The role of pathogen-sensing pathways in disease is also discussed.

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Section: Nod Receptorsmentioning

confidence: 96%

Critical role of toll-like receptors and nucleotide oligomerisation domain in the regulation of health and disease

Mitchell¹,

Paul-Clark²,

Clarke³

et al. 2007

Journal of Endocrinology

Self Cite

118

View full text Add to dashboard Cite

show abstract

“…In sepsis, the vascular endothelium barrier function becomes damaged and is lost (4). The underlying vascular smooth muscle is thus exposed and activated by pathogens, resulting in the induction of inducible nitric-oxide synthase (iNOS) and other inflammatory genes, leading to vascular collapse (5). In addition to its bactericidal function, NO derived from iNOS also acts as a potent vasodilator, which facilitates the mobilization of leukocytes into sites of infection (6).…”

Section: Recent Studies Have Demonstrated That Transcription Factor Nmentioning

confidence: 99%

Andrographolide Enhances Nuclear Factor-κB Subunit p65 Ser536 Dephosphorylation through Activation of Protein Phosphatase 2A in Vascular Smooth Muscle Cells

Hsieh

Hsu

Hsiao

et al. 2011

Journal of Biological Chemistry

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Recent studies have demonstrated that transcription factor nuclear factor (NF)-B inhibition may contribute to the protective anti-inflammatory actions of andrographolide, an abundant component of plants of the genus Andrographis. However, the precise mechanism by which andrographolide inhibits NF-B signaling remains unclear. We thus investigated the mechanism involved in andrographolide suppression of NF-B signaling in rat vascular smooth muscle cells (VSMCs) exposed to proinflammatory stimuli, LPS, and IFN-␥. Andrographolide was shown to suppress LPS/IFN-␥-induced inducible nitric-oxide synthase and matrix metalloprotease 9 expression in rat VSMCs. Andrographolide also inhibited LPS/IFN-␥-induced p65 nuclear translocation, DNA binding activity, p65 Ser 536 phosphorylation, and NF-B reporter activity. However, IKK phosphorylation and downstream inhibitory B␣ phosphorylation and degradation were not altered by the presence of andrographolide in LPS/IFN-␥-stimulated VSMCs. These andrographolide inhibitory actions could be prevented by selective inhibition of neutral sphingomyelinase and protein phosphatase 2A (PP2A). Furthermore, andrographolide was demonstrated to increase ceramide formation and PP2A activity in VSMCs and to inhibit neointimal formation in rat carotid injury models. These results suggest that andrographolide caused neutral sphingomyelinase-mediated ceramide formation and PP2A activation to dephosphorylate p65 Ser 536 , leading to NF-B inactivation and subsequent inducible nitric-oxide synthase down-regulation in rat VSMCs stimulated by LPS and IFN-␥.

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“…However, studies suggested that the actions of NOD1 vary between cell types and, unlike those seen with LPS, the in vivo effects may be independent of leukocyte activation. For instance, Cartwright and colleagues have shown that although selective activation of NOD1 in macrophages has no apparent effect, in vascular cells NOD1 activation results in the profound induction of NOSII and shock in vivo (108).…”

Section: Nlrs and Alimentioning

confidence: 99%

Pattern Recognition Receptor-Dependent Mechanisms of Acute Lung Injury

Xiang

Fan

2009

Mol Med

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Acute lung injury (ALI) that clinically manifests as acute respiratory distress syndrome is caused by an uncontrolled systemic inflammatory response resulting from clinical events including sepsis, major surgery and trauma. Innate immunity activation plays a central role in the development of ALI. Innate immunity is activated through families of related pattern recognition receptors (PRRs), which recognize conserved microbial motifs or pathogen-associated molecular patterns (PAMPs). Toll-like receptors were the first major family of PRRs discovered in mammals. Recently, NACHT–leucine-rich repeat (LRR) receptors and retinoic acid–inducible gene–like receptors have been added to the list. It is now understood that in addition to recognizing infectious stimuli, both Toll-like receptors and NACHT-LRR receptors can also respond to endogenous molecules released in response to stress, trauma and cell damage. These molecules have been termed damage-associated molecular patterns (DAMPs). It has been clinically observed for a long time that infectious and noninfectious insults initiate inflammation, so confirmation of overlapping receptor-signal pathways of activation between PAMPs and DAMPs is no surprise. This review provides an overview of the PRR-dependent mechanisms of ALI and clinical implication. Modification of PRR pathways is likely to be a logical therapeutic target for ALI/acute respiratory distress syndrome.

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Selective NOD1 Agonists Cause Shock and Organ Injury/DysfunctionIn Vivo

Abstract: Activation of NOD1 induces shock and multiple organ injury/dysfunction.

Cited by 55 publications

References 35 publications

Critical role of toll-like receptors and nucleotide oligomerisation domain in the regulation of health and disease

Critical role of toll-like receptors and nucleotide oligomerisation domain in the regulation of health and disease

Andrographolide Enhances Nuclear Factor-κB Subunit p65 Ser536 Dephosphorylation through Activation of Protein Phosphatase 2A in Vascular Smooth Muscle Cells

Pattern Recognition Receptor-Dependent Mechanisms of Acute Lung Injury

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