IRAK1 functional genetic variant affects severity of septic shock*

Toubiana, Julie; Courtine, Emilie; Pène, Frédéric; Viallon, Vivian; Asfar, Pierre; Daubin, Cédric; Rousseau, C.; Chenot, Claire; Ouaaz, Fatah; Grimaldi, David; Cariou, Alain; Chiche, Jean‐Daniel; Mira, Jean‐Paul

doi:10.1097/ccm.0b013e3181f9f9c7

Cited by 54 publications

(50 citation statements)

References 53 publications

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“…33 IRAK-1 polymorphisms resulting in increased expression and/or kinase activity are associated with more severe sepsis. 34,35 By contrast, human IRAK-4 loss-of-expression mutations increase invasive pneumococcal disease risk. 36 Downstream NF-jB signaling is critical for PRR-induced responses and its modulation changes PRR-initiated outcomes.…”

Section: Prr-induced Macrophage Functions Must Be Tightly Controlledmentioning

confidence: 89%

Negative regulation of human mononuclear phagocyte function

Hedl

Abraham

2013

Mucosal Immunology

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At mucosal surfaces, phagocytes such as macrophages coexist with microbial communities; highly controlled regulation of these interactions is essential for immune homeostasis. Pattern-recognition receptors (PRRs) are critical in recognizing and responding to microbial products, and they are subject to negative regulation through various mechanisms, including downregulation of PRR-activating components or induction of inhibitors. Insights into these regulatory mechanisms have been gained through human genetic disease-association studies, in vivo mouse studies utilizing disease models or targeted gene perturbations, and in vitro and ex vivo human cellular studies examining phagocytic cell functions. Although mouse models provide an important approach to study macrophage regulation, human and mouse macrophages exhibit differences, which must be considered when extrapolating mouse findings to human physiology. This review discusses inhibitory regulation of PRR-induced macrophage functions and the consequences of dysregulation of these functions and highlights mechanisms that have a role in intestinal macrophages and in human macrophage studies.

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Section: Prr-induced Macrophage Functions Must Be Tightly Controlledmentioning

confidence: 89%

Negative regulation of human mononuclear phagocyte function

Hedl

Abraham

2013

Mucosal Immunology

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“…In view of the large number of genes connected in some way to NF-kB signaling, we chose to limit our analysis to genes of the cytosolic members of the NF-kB pathway, excluding receptors and downstream targets. Therefore, this analysis does not include all potentially functional variants, in particular those recently published after the design of this study (43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

A Single Nucleotide Polymorphism in NF-κB Inducing Kinase Is Associated with Mortality in Septic Shock

Thair

Walley

Nakada

et al. 2011

The Journal of Immunology

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We tested the hypothesis that single nucleotide polymorphisms (SNPs) within genes of the NF-κB pathway are associated with altered clinical outcome of septic shock patients. We genotyped 59 SNPs in the NF-κB pathway in a discovery cohort of septic shock patients (St. Paul’s Hospital [SPH], N = 589), which identified the C allele of rs7222094 T/C within MAP3K14 (NF-κB inducing kinase; NIK) associated with increased 28-d mortality (uncorrected p = 0.00024, Bonferroni corrected p = 0.014). This result was replicated in a second cohort of septic shock patients (Vasopressin and Septic Shock Trial [VASST; N = 616]) in which the CC genotype of rs7222094 was associated with increased 28-d mortality (Cox regression: SPH cohort hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.12–1.64; p = 0.002 Caucasian only; and VASST cohort HR, 1.24; 95% CI, 1.00–1.52; p = 0.048 Caucasian only). Patients having the CC genotype of rs7222094 in SPH experienced more renal and hematological dysfunction (p = 0.003 and p = 0.011), while patients of the VASST cohort with the rs7222094 CC genotype showed the same trend toward more renal dysfunction. In lymphoblastoid cell lines, we found the rs7222094 genotype most strongly associated with mRNA expression of CXCL10, a chemokine regulated by NF-κB. Accordingly, we measured CXCL10 protein levels and found that the CC genotype of rs7222094 was associated with significantly lower levels than those of the TT genotype in lymphoblastoid cell lines (p < 0.05) and in septic shock patients (p = 0.017). This suggests that the CC genotype of NIK rs7222094 is associated with increased mortality and organ dysfunction in septic shock patients, perhaps due to altered regulation of NF-κB pathway genes, including CXCL10.

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“…The same concept is supported by another study showing that a polymorphism in the TNFα gene, which results in higher circulating TNFα concentrations, is associated with higher rates of MODS [38]. Other examples with various levels of predictive power are polymorphic variants in the 3’-UTR of the human leukocyte antigen G (HLA-G) gene [39], polymorphisms in the leptin and leptin receptor genes [40], a polymorphism in the promoter of the macrophage migration inhibitory factor (MIF) gene [41], the 372 T/C polymorphism of tissue inhibitor of matrix metalloproteinase (TIMP)-1 in which the T allele was associated with 16% higher mortality [42], and the 1595C/T polymorphism in the interleukin-1-receptor-associated kinase 1 (IRAK1), which was associated with the need for prolonged mechanical ventilation and decreased survival [43]. These genetic markers suggest that a dysregulation of the immune response, specifically an overactivation, is associated with decreased survival.…”

Section: Role Of Oxidative Phosphorylation In Acute Inflammationmentioning

confidence: 99%

Energy crisis: The role of oxidative phosphorylation in acute inflammation and sepsis

Lee

Hüttemann

2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

130

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Mitochondrial dysfunction is increasingly recognized as an accomplice in most of the common human diseases including cancer, neurodegeneration, diabetes, ischemia/reperfusion injury as seen in myocardial infarction and stroke, and sepsis. Inflammatory conditions, both acute and chronic, have recently been shown to affect mitochondrial function. We here discuss the role of oxidative phosphorylation (OxPhos), focusing on acute inflammatory conditions, in particular sepsis and experimental sepsis models. We discuss mitochondrial alterations, specifically suppression of oxidative metabolism and the role of mitochondrial reactive oxygen species in disease pathology. Several signaling pathways including metabolic, proliferative, and cytokine signaling affect mitochondrial function and appear to be important in inflammatory disease conditions. Cytochrome c oxidase (COX) and cytochrome c, the latter of which plays a central role in apoptosis in addition to mitochondrial respiration, serve as examples for the entire OxPhos system since they have been studied in more detail with respect to cell signaling. We propose a model in which inflammatory signaling leads to changes in the phosphorylation state of mitochondrial proteins, including Tyr304 phosphorylation of COX catalytic subunit I. This results in inhibition of OxPhos, a reduction of the mitochondrial membrane potential, and consequently a lack of energy, which can cause organ failure and death as seen in septic patients.

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IRAK1 functional genetic variant affects severity of septic shock*

Cited by 54 publications

References 53 publications

Negative regulation of human mononuclear phagocyte function

Negative regulation of human mononuclear phagocyte function

A Single Nucleotide Polymorphism in NF-κB Inducing Kinase Is Associated with Mortality in Septic Shock

Energy crisis: The role of oxidative phosphorylation in acute inflammation and sepsis

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