Cholesterol Crystals Activate the NLRP3 Inflammasome in Human Macrophages: A Novel Link between Cholesterol Metabolism and Inflammation

Chronic inflammation of the arterial wall is a key element in the pathogenesis of atherosclerosis, yet the factors that trigger and sustain the inflammation remain elusive. Inflammasomes are cytoplasmic caspase-1-activating protein complexes that promote maturation and secretion of the proinflammatory cytokines interleukin(IL)-1beta and IL-18. The most intensively studied inflammasome, NLRP3 inflammasome, is activated by diverse substances, including crystalline and particulate materials. As cholesterol crystals are abundant in atherosclerotic lesions, and IL-1beta has been linked to atherogenesis, we explored the possibility that cholesterol crystals promote inflammation by activating the inflammasome pathway.Here we show that human macrophages avidly phagocytose cholesterol crystals and store the ingested cholesterol as cholesteryl esters. Importantly, cholesterol crystals induced dose-dependent secretion of mature IL-1beta from human monocytes and macrophages. The cholesterol crystal-induced secretion of IL-1beta was caspase-1-dependent, suggesting the involvement of an inflammasome-mediated pathway. Silencing of the NLRP3 receptor, the crucial component in NLRP3 inflammasome, completely abolished crystal-induced IL-1beta secretion, thus identifying NLRP3 inflammasome as the cholesterol crystal-responsive element in macrophages. The crystals were shown to induce leakage of the lysosomal protease cathepsin B into the cytoplasm and inhibition of this enzyme reduced cholesterol crystal-induced IL-1beta secretion, suggesting that NLRP3 inflammasome activation occurred via lysosomal destabilization.The cholesterol crystal-induced inflammasome activation in macrophages may represent an important link between cholesterol metabolism and inflammation in atherosclerotic lesions

KAGRA: 2.5 Generation Interferometric Gravitational Wave Detector

The recent detections of gravitational waves (GWs) reported by LIGO/Virgocollaborations have made significant impact on physics and astronomy. A globalnetwork of GW detectors will play a key role to solve the unknown nature of thesources in coordinated observations with astronomical telescopes and detectors.Here we introduce KAGRA (former name LCGT; Large-scale Cryogenic Gravitationalwave Telescope), a new GW detector with two 3-km baseline arms arranged in theshape of an "L", located inside the Mt. Ikenoyama, Kamioka, Gifu, Japan.KAGRA's design is similar to those of the second generations such as AdvancedLIGO/Virgo, but it will be operating at the cryogenic temperature with sapphiremirrors. This low temperature feature is advantageous for improving thesensitivity around 100 Hz and is considered as an important feature for thethird generation GW detector concept (e.g. Einstein Telescope of Europe orCosmic Explorer of USA). Hence, KAGRA is often called as a 2.5 generation GWdetector based on laser interferometry. The installation and commissioning ofKAGRA is underway and its cryogenic systems have been successfully tested inMay, 2018. KAGRA's first observation run is scheduled in late 2019, aiming tojoin the third observation run (O3) of the advanced LIGO/Virgo network. In thiswork, we describe a brief history of KAGRA and highlights of main feature. Wealso discuss the prospects of GW observation with KAGRA in the era of O3. Whenoperating along with the existing GW detectors, KAGRA will be helpful to locatea GW source more accurately and to determine the source parameters with higherprecision, providing information for follow-up observations of a GW triggercandidate

Vibration isolation system with a compact damping system for power recycling mirrors of KAGRA

A vibration isolation system called the Type-Bp system used for power recycling mirrors has been developed for KAGRA, the interferometric gravitational-wave observatory in Japan. A suspension of the Type-Bp system passively isolates an optic from seismic vibration using three main pendulum stages equipped with two vertical vibration isolation systems. A compact reaction mass around each of the main stages allows for achieving sufficient damping performance with a simple feedback as well as vibration isolation ratio. Three Type-Bp systems were installed in KAGRA, and were proved to satisfy the requirements on the damping performance, and also on estimated residual displacement of the optics

Application of independent component analysis to the iKAGRA data

We apply independent component analysis (ICA) to real data from a gravitational wave detector for the first time. Specifically, we use the iKAGRA data taken in April 2016, and calculate the correlations between the gravitational wave strain channel and 35 physical environmental channels. Using a couple of seismic channels which are found to be strongly correlated with the strain, we perform ICA. Injecting a sinusoidal continuous signal in the strain channel, we find that ICA recovers correct parameters with enhanced signal-to-noise ratio, which demonstrates the usefulness of this method. Among the two implementations of ICA used here, we find the correlation method yields the optimal results for the case of environmental noise acting on the strain channel linearly

Ethanol Inhibits Activation of NLRP3 and AIM2 Inflammasomes in Human Macrophages- A Novel Anti-Inflammatory Action of Alcohol

Peer reviewe

Interleukin-1 beta has atheroprotective effects in advanced atherosclerotic lesions of mice

Despite decades of research, our understanding of the processes controlling late-stage atherosclerotic plaque stability remains poor. A prevailing hypothesis is that reducing inflammation may improve advanced plaque stability, as recently tested in the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial, in which post-myocardial infarction subjects were treated with an IL-1β antibody. Here, we performed intervention studies in which smooth muscle cell (SMC) lineage-tracing Apoe-/- mice with advanced atherosclerosis were treated with anti-IL-1β or IgG control antibodies. Surprisingly, we found that IL-1β antibody treatment between 18 and 26 weeks of Western diet feeding induced a marked reduction in SMC and collagen content, but increased macrophage numbers in the fibrous cap. Moreover, although IL-1β antibody treatment had no effect on lesion size, it completely inhibited beneficial outward remodeling. We also found that SMC-specific knockout of Il1r1 (encoding IL-1 receptor type 1) resulted in smaller lesions nearly devoid of SMCs and lacking a fibrous cap, whereas macrophage-selective loss of IL-1R1 had no effect on lesion size or composition. Taken together, these results show that IL-1β has multiple beneficial effects in late-stage murine atherosclerosis, including promotion of outward remodeling and formation and maintenance of an SMC- and collagen-rich fibrous cap

Application of independent component analysis to the iKAGRA data

We apply independent component analysis (ICA) to real data from a gravitational wave detector for the first time. Specifically, we use the iKAGRA data taken in April 2016, and calculate the correlations between the gravitational wave strain channel and 35 physical environmental channels. Using a couple of seismic channels which are found to be strongly correlated with the strain, we perform ICA. Injecting a sinusoidal continuous signal in the strain channel, we find that ICA recovers correct parameters with enhanced signal-to-noise ratio, which demonstrates the usefulness of this method. Among the two implementations of ICA used here, we find the correlation method yields the optimal results for the case of environmental noise acting on the strain channel linearly