NLRP1 was the first NOD-like receptor described to form an inflammasome, recruiting ASC to activate caspase-1, which processes interleukin-1β and interleukin-18 to their active form. A wealth of new ...genetic information has now redefined our understanding of this innate immune sensor. Specifically, rare loss-of-function variants in the N-terminal pyrin domain indicate that this part of NLRP1 is autoinhibitory and normally acts to prevent a familial autoinflammatory skin disease associated with cancer. In the absence of a ligand to trigger human NLRP1, these mutations have now confirmed the requirement of NLRP1 autolytic cleavage within the FIIND domain, which had previously been implicated in NLRP1 activation. Autolytic cleavage generates a C-terminal fragment of NLRP1 containing the CARD domain which then forms an ASC-dependent inflammasome. The CARD domain as an inflammasome linker is consistent with the observation that under some conditions, particularly for mouse NLRP1, caspase-1 can be engaged directly, and although it is no longer processed, it is still capable of producing mature IL-1β. Additional rare variants in a linker region between the LRR and FIIND domains of NLRP1 also cause autoinflammatory disease in both humans and mice. This new genetic information is likely to provide for more mechanistic insight in the years to come, contributing to our understanding of how NLRP1 functions as an innate immune sensor of infection and predisposes to autoimmune or autoinflammatory diseases.
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•Genetic variants in NLRP1 lead to autoimmune and autoinflammatory diseases in both humans and mice.•NLRP1 N-terminal domain (PYD in humans) is autoinhibitory, whereas the C-terminal cleavage fragment containing the CARD domain engages an ASC-dependent inflammasome.•Disease-associated mutations in the NLRP1 linker region between NACHT and LRR domains suggest additional mechanisms of autoinhibition.
The inflammasome is a critical molecular complex that activates interleukin-1 driven inflammation in response to pathogen- and danger-associated signals. Germline mutations in the inflammasome sensor ...NLRP1 cause Mendelian systemic autoimmunity and skin cancer susceptibility, but its endogenous regulation remains less understood. Here we use a proteomics screen to uncover dipeptidyl dipeptidase DPP9 as a novel interacting partner with human NLRP1 and a related inflammasome regulator, CARD8. DPP9 functions as an endogenous inhibitor of NLRP1 inflammasome in diverse primary cell types from human and mice. DPP8/9 inhibition via small molecule drugs and CRISPR/Cas9-mediated genetic deletion specifically activate the human NLRP1 inflammasome, leading to ASC speck formation, pyroptotic cell death, and secretion of cleaved interleukin-1β. Mechanistically, DPP9 interacts with a unique autoproteolytic domain (Function to Find Domain (FIIND)) found in NLRP1 and CARD8. This scaffolding function of DPP9 and its catalytic activity act synergistically to maintain NLRP1 in its inactive state and repress downstream inflammasome activation. We further identified a single patient-derived germline missense mutation in the NLRP1 FIIND domain that abrogates DPP9 binding, leading to inflammasome hyperactivation seen in the Mendelian autoinflammatory disease Autoinflammation with Arthritis and Dyskeratosis. These results unite recent findings on the regulation of murine Nlrp1b by Dpp8/9 and uncover a new regulatory mechanism for the NLRP1 inflammasome in primary human cells. Our results further suggest that DPP9 could be a multifunctional inflammasome regulator involved in human autoinflammatory diseases.
Cytoplasmic accumulation of TDP-43 is a disease hallmark for many cases of amyotrophic lateral sclerosis (ALS), associated with a neuroinflammatory cytokine profile related to upregulation of nuclear ...factor κB (NF-κB) and type I interferon (IFN) pathways. Here we show that this inflammation is driven by the cytoplasmic DNA sensor cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) when TDP-43 invades mitochondria and releases DNA via the permeability transition pore. Pharmacologic inhibition or genetic deletion of cGAS and its downstream signaling partner STING prevents upregulation of NF-κB and type I IFN induced by TDP-43 in induced pluripotent stem cell (iPSC)-derived motor neurons and in TDP-43 mutant mice. Finally, we document elevated levels of the specific cGAS signaling metabolite cGAMP in spinal cord samples from patients, which may be a biomarker of mtDNA release and cGAS/STING activation in ALS. Our results identify mtDNA release and cGAS/STING activation as critical determinants of TDP-43-associated pathology and demonstrate the potential for targeting this pathway in ALS.
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•TDP-43 enters mitochondria, triggers mtDNA release via the mPTP•TDP-43-induced cytosolic mtDNA accumulation activates the cGAS/STING pathway•Evidence of cytoplasmic mtDNA was found in ALS patient cells and disease models•Blocking STING prevents inflammation and neurodegeneration in vitro and in vivo
TDP-43 causes inflammation in ALS by stimulating mitochondrial DNA release, which is subsequently sensed by the cytosolic cGAS/STING pathway, suggesting that inhibition of cGAS/STING could help alleviate inflammation-related damage in ALS.
Genetic lesions in X‐linked inhibitor of apoptosis (XIAP) pre‐dispose humans to cell death–associated inflammatory diseases, although the underlying mechanisms remain unclear. Here, we report that ...two patients with XIAP deficiency–associated inflammatory bowel disease display increased inflammatory IL‐1β maturation as well as cell death–associated caspase‐8 and Gasdermin D (GSDMD) processing in diseased tissue, which is reduced upon patient treatment. Loss of XIAP leads to caspase‐8‐driven cell death and bioactive IL‐1β release that is only abrogated by combined deletion of the apoptotic and pyroptotic cell death machinery. Namely, extrinsic apoptotic caspase‐8 promotes pyroptotic GSDMD processing that kills macrophages lacking both inflammasome and apoptosis signalling components (caspase‐1, ‐3, ‐7, ‐11 and BID), while caspase‐8 can still cause cell death in the absence of both GSDMD and GSDME when caspase‐3 and caspase‐7 are present. Neither caspase‐3 and caspase‐7‐mediated activation of the pannexin‐1 channel, or GSDMD loss, prevented NLRP3 inflammasome assembly and consequent caspase‐1 and IL‐1β maturation downstream of XIAP inhibition and caspase‐8 activation, even though the pannexin‐1 channel was required for NLRP3 triggering upon mitochondrial apoptosis. These findings uncouple the mechanisms of cell death and NLRP3 activation resulting from extrinsic and intrinsic apoptosis signalling, reveal how XIAP loss can co‐opt dual cell death programs, and uncover strategies for targeting the cell death and inflammatory pathways that result from XIAP deficiency.
Synopsis
XIAP deficiency causes hemophagocytic lymphohistiocytosis and Crohn's disease. Analysis of XIAP‐deficient patients and cellular studies show that apoptotic caspases and GSDMD act redundantly downstream of caspase‐8 to cause excess cell death and IL‐1β release.
XIAP deficiency increases cleaved caspase‐8 and GSDMD in mucosal tissue and cells
Crosstalk in apoptosis and pyroptosis sensitises cells to caspase‐8‐driven death and IL‐1β activation upon XIAP inhibition
Pannexin‐1 and GSDMD are dispensable for NLRP3 inflammasome formation downstream of caspase‐8
Pannexin‐1 cleavage by caspase‐3 and caspase‐7 is required for efficient NLRP3 activation following intrinsic apoptosis
Loss of XIAP leads to the activation of multiple cell death pathways to promote inflammatory diseases.
Emergent evidence has shown that abnormal buildup of stray self-nucleic acids is a pathological feature observed across many neurodegenerative conditions. Here, we discuss how these self-nucleic ...acids act as a driver of disease by triggering harmful inflammatory responses. Understanding these pathways and targeting them has the potential to prevent neuronal death at the early stages of disease.
To save manufacturing cost, most color digital video cameras employ a single-sensor technology with a red-green- blue (RGB) color filter array (CFA) to capture real-world scenes. Due to only one ...primary color measured at each pixel location, the captured videos are usually referred to as the mosaic videos. For the purposes of economical storage and transmission, it is very important to achieve a good tradeoff between the quality and bitrate when compressing mosaic videos with different RGB-CFA structures. In this paper, based on mathematical optimization technique, a novel chroma subsampling strategy is presented for compressing mosaic videos with arbitrary RGB-CFA structures in H.264/AVC and High Efficiency Video Coding (HEVC). For each 2 × 2 YUV block to be subsampled with 4:2:0 format, the proposed strategy determines the proper sampled U and V components by minimizing, prior to compression, the quality distortion between the original colocated mosaic block and the mosaic block conversed from the current subsampled YUV block. Through the mathematical optimization formulated in the proposed strategy, the significance of the sampled U and V components for reconstructing R, G, and B pixels can be simultaneously taken into consideration. The experimental results demonstrate that the proposed chroma subsampling strategy has the best quality and bitrate tradeoff at a similar execution time requirement for compressing mosaic videos with arbitrary RGB-CFA structures in H.264/AVC and HEVC compared with the state-of-the-art ones by Chen et al. and Yang et al. as well as the three commonly used ones.
Background Should all out-of-hospital cardiac arrest (OHCA) patients be directly transported to cardiac arrest centers (CACs) remains under debate. Our study evaluated the impacts of different ...transport time and destination hospital on the outcomes of OHCA patients. Methods and Results Data were collected from 6655 OHCA patients recorded in the regional prospective OHCA registry database of Taoyuan City, Taiwan, between January 2012 and December 2016. Patients were matched on propensity score, which left 5156 patients, 2578 each in the CAC and non-CAC groups. Transport time was dichotomized into <8 and ≥8 minutes. The relations between the transport time to CACs and good neurological outcome at discharge and survival to discharge were investigated. Of the 5156 patients, 4215 (81.7%) presented with nonshockable rhythms and 941 (18.3%) presented with shockable rhythms. Regardless of transport time, transportation to a CAC increased the likelihoods of survival to discharge (<8 minutes: adjusted odds ratio aOR, 1.95; 95% CI, 1.11-3.41; ≥8 minutes: aOR, 1.92; 95% CI, 1.25-2.94) and good neurological outcome at discharge (<8 minutes: aOR, 2.70; 95% CI, 1.40-5.22; ≥8 minutes: aOR, 2.20; 95% CI, 1.29-3.75) in OHCA patients with shockable rhythms but not in patients with nonshockable rhythms. Conclusions OHCA patients with shockable rhythms transported to CACs demonstrated higher probabilities of survival to discharge and a good neurological outcome at discharge. Direct ambulance delivery to CACs should thus be considered, particularly when OHCA patients present with shockable rhythms.
Coatomer complex I (COPI) mediates retrograde vesicular trafficking from Golgi to the endoplasmic reticulum (ER) and within Golgi compartments. Deficiency in subunit alpha causes COPA syndrome and is ...associated with type I IFN signalling, although the upstream innate immune sensor involved was unknown. Using in vitro models we find aberrant activation of the STING pathway due to deficient retrograde but probably not intra-Golgi transport. Further we find the upstream cytosolic DNA sensor cGAS as essentially required to drive type I IFN signalling. Genetic deletion of COPI subunits COPG1 or COPD similarly induces type I IFN activation in vitro, which suggests that inflammatory diseases associated with mutations in other COPI subunit genes may exist. Finally, we demonstrate that inflammation in COPA syndrome patient peripheral blood mononuclear cells and COPI-deficient cell lines is ameliorated by treatment with the small molecule STING inhibitor H-151, suggesting targeted inhibition of the cGAS/STING pathway as a promising therapeutic approach.
Public access defibrillation (PAD) programs have been implemented globally over the past decade. Although PAD can substantially increase the survival of cardiac arrest, PAD use remains low. This ...study aimed to evaluate whether drawing upon the successful experiences of dispatcher-assisted cardiopulmonary resuscitation programs would increase the use of PAD in dispatcher-assisted PAD programs.
This study using a before-and-after design was conducted in Taoyuan City using a local out-of-hospital cardiac arrest registry system and data of dispatcher performance derived from audio recordings. The primary outcomes were the rate of bystander PAD use, sustained return of spontaneous circulation, survival to discharge, and favorable neurological outcomes. The secondary outcomes were the performance of dispatchers in terms of PAD instruction and dispatcher-assisted cardiopulmonary resuscitation administration, the time interval indicators of dispatcher-assisted cardiopulmonary resuscitation. A total of 1159 patients were included and divided into 2 groups: the before-run-in group (502 patients) and the after-run-in group (657 patients). No significant difference was observed between the 2 groups in terms of baseline characteristics. The rate of PAD use in the after-run-in group significantly increased from 5.0% to 8.7% (
=0.015). The rate of favorable neurological outcomes increased from 4.4% to 5.9%, which was not a statistically significant difference. Compared with the before-run-in group, the rate of successful automated external defibrillator acquisition was 13.5% in the after-run-in group (
<0.001).
Implementing a dispatcher-assisted PAD protocol in a municipality setting significantly increased bystander PAD use without affecting dispatcher performance in out-of-hospital cardiac arrest recognition, cardiopulmonary resuscitation instruction, or dispatcher-assisted cardiopulmonary resuscitation time indicators.
Cardiopulmonary resuscitation (CPR) training and its quality are critical in improving the survival rate of cardiac arrest. This randomized controlled study investigated the efficacy of a newly ...developed CPR training program for the public in a Taiwanese setting. A total of 832 adults were randomized to either a traditional or blended (18-minute e-learning plus 30-minute hands-on) compression-only CPR training program. The primary outcome was compression depth. Secondary outcomes included CPR knowledge test, practical test, quality of CPR performance, and skill retention. The mean compression depth was 5.21 cm and 5.24 cm in the blended and traditional groups, respectively. The mean difference in compression depth between groups was -0.04 (95% confidence interval -0.13 to infinity), demonstrating that the blended CPR training program was non-inferior to the traditional CPR training program in compression depth after initial training. Secondary outcome results were comparable between groups. Although the mean compression depth and rate were guideline-compliant, only half of the compressions were delivered with adequate depth and rate in both groups. CPR knowledge and skill retained similarly in both groups at 6 and 12 months after training. The blended CPR training program was non-inferior to the traditional CPR training program. However, there is still room for improvement in optimizing initial skill performance as well as skill retention. Clinical Trial Registration: NCT03586752; www.clinicaltrial.gov.
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