Truncating NFKB1 variants cause combined NLRP3 inflammasome activation and type I interferon signaling and predispose to necrotizing fasciitis.

In monogenic autoinflammatory diseases, mutations in genes regulating innate immune responses often lead to uncontrolled activation of inflammasome pathways or the type I interferon (IFN-I) response. We describe a mechanism of autoinflammation potentially predisposing patients to life-threatening necrotizing soft tissue inflammation. Six unrelated families are identified in which affected members present with necrotizing fasciitis or severe soft tissue inflammations. Exome sequencing reveals truncating monoallelic loss-of-function variants of nuclear factor κ light-chain enhancer of activated B cells (NFKB1) in affected patients. In patients' macrophages and in NFKB1-variant-bearing THP-1 cells, activation increases both interleukin (IL)-1ß secretion and IFN-I signaling. Truncation of NF-κB1 impairs autophagy, accompanied by the accumulation of reactive oxygen species and reduced degradation of inflammasome receptor nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein 3 (NLRP3), and Toll/IL-1 receptor domain-containing adaptor protein inducing IFN-ß (TRIF), thus leading to combined excessive inflammasome and IFN-I activity. Many of the patients respond to anti-inflammatory treatment, and targeting IL-1ß and/or IFN-I signaling could represent a therapeutic approach for these patients.

Native and oxidised lipoproteins negatively regulate the serum amyloid A-induced NLRP3 inflammasome activation in human macrophages.

OBJECTIVES: The NLRP3 inflammasome plays a key role in arterial wall inflammation. In this study, we elucidated the role of serum lipoproteins in the regulation of NLRP3 inflammasome activation by serum amyloid A (SAA) and other inflammasome activators. METHODS: The effect of lipoproteins on the NLRP3 inflammasome activation was studied in primary human macrophages and THP-1 macrophages. The effect of oxidised low-density lipoprotein (LDL) was examined in an in vivo mouse model of SAA-induced peritoneal inflammation. RESULTS: Native and oxidised high-density lipoproteins (HDL3) and LDLs inhibited the interaction of SAA with TLR4. HDL3 and LDL inhibited the secretion of interleukin (IL)-1ß and tumor necrosis factor by reducing their transcription. Oxidised forms of these lipoproteins reduced the secretion of mature IL-1ß also by inhibiting the activation of NLRP3 inflammasome induced by SAA, ATP, nigericin and monosodium urate crystals. Specifically, oxidised LDL was found to inhibit the inflammasome complex formation. No cellular uptake of lipoproteins was required, nor intact lipoprotein particles for the inhibitory effect, as the lipid fraction of oxidised LDL was sufficient. The inhibition of NLRP3 inflammasome activation by oxidised LDL was partially dependent on autophagy. Finally, oxidised LDL inhibited the SAA-induced peritoneal inflammation and IL-1ß secretion in vivo. CONCLUSIONS: These findings reveal that both HDL3 and LDL inhibit the proinflammatory activity of SAA and this inhibition is further enhanced by lipoprotein oxidation. Thus, lipoproteins possess major anti-inflammatory functions that hinder the NLRP3 inflammasome-activating signals, particularly those exerted by SAA, which has important implications in the pathogenesis of cardiovascular diseases.

Clinical and sonographic risk factors and complications of shoulder dystocia - a case-control study with parity and gestational age matched controls.

OBJECTIVES: To examine the clinical risk factors and complications of shoulder dystocia today and to evaluate ultrasound methods predicting it. STUDY DESIGN: Retrospective, matched case-control study at a University Hospital with 5000 annual deliveries. The study population consisted of 152 deliveries complicated by shoulder dystocia over a period of 8.5 years (January 2004-June 2012) and 152 controls matched for gestational age and parity. The data was collected from the medical records of mothers and children and analyzed by conditional logistic regression. Incidences and odds ratios were calculated for risk factors and complications. Antenatal ultrasound data was analyzed when available by conditional logistic regression to test for significant differences between study groups. RESULTS: Birthweight (OR 12.1 for ≥4000 g; 95% CI 4.18-35.0) and vacuum extraction (OR 3.98; 95% CI 1.25-12.7) remained the most significant clinical risk factors. Only a trend of an association of pregestational or gestational diabetes was noticed (OR 1.87; 95% CI 0.997-3.495, probability of type II error 51%). Of the complications of shoulder dystocia the incidence of brachial plexus palsies was high (40%). Antenatal ultrasound method based on the difference between abdominal and biparietal diameters had a significant difference between cases and controls. CONCLUSIONS: The impact of diabetes as a risk factor has diminished, which may reflect improved screening and treatment. Antenatal ultrasound methods are showing some promise, but the predictive value of ultrasound alone is probably low.