Association of REL polymorphisms and outcome of patients with septic shock

International audienceBackground: cRel, a subunit of NF‑κB, is implicated in the inflammatory response observed in autoimmune disease. Hence, knocked‑out mice for cRel had a significantly higher mortality, providing new and important functions of cRel in the physiopathology of septic shock. Whether genetic variants in the human REL gene are associated with severity of septic shock is unknown. Methods: We genotyped a population of 1040 ICU patients with septic shock and 855 ICU controls for two known polymorphisms of REL; REL rs842647 and REL rs13031237. Outcome of patients according to the presence of REL variant alleles was compared. Results: The distribution of REL variant alleles was not significantly different between patients and controls. Among the septic shock group, REL rs13031237*T minor allele was not associated with worse outcome. In contrast, REL rs842647*G minor allele was significantly associated with more multi‑organ failure and early death [OR 1.4; 95 % CI (1.02–1.8)]. Conclusion: In a large ICU population, we report a significant clinical association between a variation in the human REL gene and severity and mortality of septic shock, suggesting for the first time a new insight into the role of cRel in response to infection in humans

IRAK1 functional genetic variant affects severity of septic shock

International audienceObjectives: Excessive inflammation is closely related to severity and outcome of sepsis. Because interleukin-1-receptor-associated kinase 1 is a key signaling protein in the activation of NF-κB during infection, we aimed to evaluate the effect of functionally relevant haplotypes of IRAK1 on severity, development of acute lung injury, and mortality in septic shock.Design: Prospective, observational, cohort study. Setting: Three medical intensive care units in three French university hospitals. Patients: Eight hundred forty-three Caucasian patients with septic shock and 800 sex-matched Caucasian control subjects were enrolled. Interventions: Patients were genotyped for the IRAK1–1595C/T polymorphism, which tagged the IRAK1 functional haplotype. Measurements and Main Results: No significant differences in IRAK1 genotypes were seen between patients and control subjects. Among the septic shock group, the IRAK1 variant haplotype was significantly associated with the need for prolonged mechanical ventilation (p = .02). In a prespecified subgroup, this genetic risk was most severe in the youngest patients (age &lt;65 yrs, p = .005). Furthermore, in the more severe subgroup of patients, a higher mortality rate was found in patients carrying the IRAK-1 variant haplotype as compared with the wild type (p = .02) (odds ratio, 2.1; 95% confidence interval, 1.1–4.8). Conclusions: The IRAK1 variant haplotype is associated with prolonged ventilation in septic shock. In the future, the IRAK1–1595C/T polymorphism might be included in scores such as PIRO (predisposition, insult, response, and organ dysfunction) to adapt preventive and therapeutic interventions in the intensive care unit.</p

Toll-Like Receptors 2 and 4 Contribute to Sepsis-Induced Depletion of Spleen Dendritic Cells▿

Depletion of dendritic cells (DC) in secondary lymphoid organs is a hallmark of sepsis-induced immune dysfunction. In this setting, we investigated if Toll-like receptor (TLR)-dependent signaling might modulate the maturation process and the survival of DC. Using a model of sublethal polymicrobial sepsis induced by cecal ligation and puncture, we investigated the quantitative and functional features of spleen DC in wild-type, TLR2−/−, TLR4−/−, and TLR2−/− TLR4−/− mice. By 24 h, a decrease in the relative percentage of CD11chigh spleen DC occurred in wild-type mice but was prevented in TLR2−/−, TLR4−/−, and TLR2−/− TLR4−/− mice. In wild-type mice, sepsis dramatically affected both CD11c+ CD8α+ and CD11c+ CD8α− subsets. In all three types of knockout mice studied, the CD11c+ CD8α+ subset followed a depletion pattern similar to that for wild-type mice. In contrast, the loss of CD11c+ CD8α− cells was attenuated in TLR2−/− and TLR4−/− mice and completely prevented in TLR2−/− TLR4−/− mice. Accordingly, apoptosis of spleen DC was increased in septic wild-type mice and inhibited in knockout mice. In addition we characterized the functional features of spleen DC obtained from septic mice. As shown by increased expression of major histocompatibility complex class II and CD86, polymicrobial sepsis induced maturation of DC, with subsequent increased capacity to prime T lymphocytes, similarly in wild-type and knockout mice. In response to CpG DNA stimulation, production of interleukin-12 was equally impaired in DC obtained from wild-type and knockout septic mice. In conclusion, although dispensable for the DC maturation process, TLR2 and TLR4 are involved in the mechanisms leading to depletion of spleen DC following polymicrobial sepsis

Critical Role of cRel Subunit of NF-κB in Sepsis Survival ▿ †

NF-κB is a critical regulator of gene expression during severe infections. NF-κB comprises homo- and heterodimers of proteins from the Rel family. Among them, p50 and p65 have been clearly implicated in the pathophysiology of sepsis. In contrast, the role of cRel in sepsis is still controversial and has been poorly studied in single-pathogen infections. We aimed to investigate the consequences of cRel deficiency in a cecal ligation and puncture (CLP) model of sepsis. We have approached the underlying mechanisms of host defense by analyzing bacterial clearance, systemic inflammation, and the distribution of spleen dendritic cell subsets. Moreover, by using a genome-wide technology, we have also analyzed the CLP-induced modifications in gene expression profiles both in wild-type (wt) and in rel−/− mice. The absence of cRel enhances mortality due to polymicrobial sepsis. Despite normal pathogen clearance, cRel deficiency leads to an altered systemic inflammatory response associated with a sustained loss of the spleen lymphoid dendritic cells. Furthermore, a whole-blood microarray study reveals that the differential outcome between wt and rel−/− mice during sepsis is preceded by remarkable changes in the expression of hundreds of genes involved in aspects of host-pathogen interaction, such as host survival and lipid metabolism. In conclusion, cRel is a key NF-κB member required for host antimicrobial defenses and a regulatory transcription subunit that controls the inflammatory and immune responses in severe infection