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Parkinson's disease is characterized by accumulation of α-synuclein (αSyn). Release of oligomeric/fibrillar αSyn from damaged neurons may potentiate neuronal death in part via microglial activation. Heretofore, it remained unknown if oligomeric/fibrillar αSyn could activate the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome in human microglia and whether anti-αSyn antibodies could prevent this effect. Here, we show that αSyn activates the NLRP3 inflammasome in human induced pluripotent stem cell (hiPSC)-derived microglia (hiMG) via dual stimulation involving Toll-like receptor 2 (TLR2) engagement and mitochondrial damage. In vitro, hiMG can be activated by mutant (A53T) αSyn secreted from hiPSC-derived A9-dopaminergic neurons. Surprisingly, αSyn-antibody complexes enhanced rather than suppressed inflammasome-mediated interleukin-1β (IL-1β) secretion, indicating these complexes are neuroinflammatory in a human context. A further increase in inflammation was observed with addition of oligomerized amyloid-β peptide (Aβ) and its cognate antibody. In vivo, engraftment of hiMG with αSyn in humanized mouse brain resulted in caspase-1 activation and neurotoxicity, which was exacerbated by αSyn antibody. These findings may have important implications for antibody therapies aimed at depleting misfolded/aggregated proteins from the human brain, as they may paradoxically trigger inflammation in human microglia.

Excessive alcohol consumption induces intestinal dysbiosis of the gut microbiome and reduces gut epithelial integrity. This often leads to portal circulation-mediated translocation of gut-derived microbial products, such as lipopolysaccharide (LPS), to the liver, where these products engage Toll-like receptor 4 (TLR4) and initiate hepatic inflammation, which promotes alcoholic liver disease (ALD). Although the key self-destructive process of autophagy has been well-studied in hepatocytes, its role in macrophages during ALD pathogenesis remains elusive. Using WT and myeloid cell-specific autophagy-related 7 (Atg7) knockout (Atg7 ΔMye) mice, we found that chronic ethanol feeding for 6 weeks plus LPS injection enhances serum alanine aminotransferase and IL-1β levels and augments hepatic C-C motif chemokine ligand 5 (CCL5) and C-X-C motif chemokine ligand 10 (CXCL10) expression in WT mice, a phenotype that was further exacerbated in Atg7 ΔMye mice. Atg7 ΔMye macrophages exhibited defective mitochondrial respiration and displayed elevated mitochondrial reactive oxygen species production and inflammasome activation relative to WT cells. Interestingly, compared with WT cells, Atg7 ΔMye macrophages also had a drastically increased abundance and nuclear translocation of interferon regulatory factor 1 (IRF1) after LPS stimulation. Mechanistically, LPS induced co-localization of IRF1 with the autophagy adaptor p62 and the autophagosome, resulting in subsequent IRF1 degradation. However, upon p62 silencing or Atg7 deletion, IRF1 started to accumulate in autophagy-deficient macrophages and translocated into the nucleus, where it induced CCL5 and CXCL10 expression. In conclusion, macrophage autophagy protects against ALD by promoting IRF1 degradation and removal of damaged mitochondria, limiting macrophage activation and inflammation.

Choline is a vitamin-like nutrient that is taken up via specific transporters and metabolized by choline kinase, which converts it to phosphocholine needed for de novo synthesis of phosphatidylcholine (PC), the main phospholipid of cellular membranes. We found that Toll-like receptor (TLR) activation enhances choline uptake by macrophages and microglia through induction of the choline transporter CTL1. Inhibition of CTL1 expression or choline phosphorylation attenuated NLRP3 inflammasome activation and IL-1β and IL-18 production in stimulated macrophages. Mechanistically, reduced choline uptake altered mitochondrial lipid profile, attenuated mitochondrial ATP synthesis, and activated the energy sensor AMP-activated protein kinase (AMPK). By potentiating mitochondrial recruitment of DRP1, AMPK stimulates mitophagy, which contributes to termination of NLRP3 inflammasome activation. Correspondingly, choline kinase inhibitors ameliorated acute and chronic models of IL-1β-dependent inflammation.

Background & aimsAlthough there are associations among oxidative stress, reduced nicotinamide adenine dinucleotide phosphate oxidase (NOX) activation, and hepatocellular carcinoma (HCC) development, it is not clear how NOX contributes to hepatocarcinogenesis. We studied the functions of different NOX proteins in mice after administration of a liver carcinogen.MethodsFourteen-day-old Nox1-/- mice, Nox4-/- mice, Nox1-/-Nox4-/- (double-knockout) mice, and wild-type (WT) C57BL/6 mice were given a single intraperitoneal injection of diethylnitrosamine (DEN) and liver tumors were examined at 9 months. We also studied the effects of DEN in mice with disruption of Nox1 specifically in hepatocytes (Nox1ΔHep), hepatic stellate cells (Nox1ΔHep), or macrophages (Nox1ΔMac). Some mice were also given injections of the NOX1-specific inhibitor ML171. To study the acute effects of DEN, 8-12-week-old mice were given a single intraperitoneal injection, and liver and serum were collected at 72 hours. Liver tissues were analyzed by histologic examination, quantitative polymerase chain reaction, and immunoblots. Hepatocytes and macrophages were isolated from WT and knockout mice and analyzed by immunoblots.ResultsNox4-/- mice and WT mice developed liver tumors within 9 months after administration of DEN, whereas Nox1-/- mice developed 80% fewer tumors, which were 50% smaller than those of WT mice. Nox1ΔHep and Nox1ΔHSC mice developed liver tumors of the same number and size as WT mice, whereas Nox1ΔMac developed fewer and smaller tumors, similar to Nox1-/- mice. After DEN injection, levels of tumor necrosis factor, interleukin 6 (IL6), and phosphorylated signal transducer and activator of transcription 3 were increased in livers from WT, but not Nox1-/- or Nox1ΔMac, mice. Conditioned medium from necrotic hepatocytes induced expression of NOX1 in cultured macrophages, followed by expression of tumor necrosis factor, IL6, and other inflammatory cytokines; this medium did not induce expression of IL6 or cytokines in Nox1ΔMac macrophages. WT mice given DEN followed by ML171 developed fewer and smaller liver tumors than mice given DEN followed by vehicle.ConclusionsIn mice given injections of a liver carcinogen (DEN), expression of NOX1 by macrophages promotes hepatic tumorigenesis by inducing the production of inflammatory cytokines. We propose that upon liver injury, damage-associated molecular patterns released from dying hepatocytes activate liver macrophages to produce cytokines that promote tumor development. Strategies to block NOX1 or these cytokines might be developed to slow hepatocellular carcinoma progression.

Purpose: To compare the 26-week cost-effectiveness of adalimumab-corticosteroids (ADA-CS) and cyclosporine-corticosteroids (CSA-CS) for Vogt-Koyanagi-Harada (VKH). Methods: A preplanned cost-effectiveness analysis based on the per-protocol population of a randomized-controlled trial. VKH subjects were randomized to receive either cyclosporine (100-200 mg daily) combined with corticosteroids or adalimumab (40 mg twice monthly) combined with corticosteroids. The primary outcome of this cost-effectiveness study was the incremental cost-effectiveness ratio (ICER). Costs and quality-adjusted life-years (QALYs) data were calculated by the medical records and health utility, respectively. Subgroup (early and late-phase VKH) analysis and sensitivity analyses were performed. Results: The ICER at 26 weeks was $62,425/QALY for the total participants. Compared to the CSA-CS group, costs in the ADA-CS group were more expensive (mean difference [ΔA-C]: $2,497) with more gains in QALYs (mean difference [ΔA-C]: 0.04). The probability of ADA-CS being cost-effective was 0.17 and 0.41 at willingness to pay (WTP) thresholds of $12,000/QALY and $36,000/QALY, respectively. Subgroup analysis and sensitivity analyses showed consistent findings with the primary analysis. Conclusions: Regardless of early or late-phase VKH, the CSA-CS strategy may be recommended as the preferred initial choice for the majority of VKH. [ABSTRACT FROM AUTHOR]

Preventing work-related musculoskeletal disorders (WMSDs) is crucial in reducing their impact on individuals and society. However, the existing mainstream 2D image-based approach is insufficient in capturing the complex 3D movements and postures involved in many occupational tasks. To address this, an improved deep learning-based rapid entire body assessment (REBA) method has been proposed. The method takes working videos as input and automatically outputs the corresponding REBA score through 3D pose reconstruction. The proposed method achieves an average precision of 94.7% on real-world data, which is comparable to that of ergonomic experts. Furthermore, the method has the potential to be applied across a wide range of industries as it has demonstrated good generalisation in multiple scenarios. The proposed method offers a promising solution for automated and accurate risk assessment of WMSDs, with implications for various industries to ensure the safety and well-being of workers. PRACTITIONER SUMMARY: This paper proposes a deep learning-based improved rapid entire body assessment (REBA) method for assessing work-related musculoskeletal disorders (WMSDs) risks using 3D pose reconstruction from videos, achieving 94.7% precision, comparable to ergonomic experts, with potential applications across various industries. [ABSTRACT FROM AUTHOR]

Objective Diagnostic pitfalls often arise in the community because of potentially misleading similarities between juvenile idiopathic arthritis (JIA) and Blau syndrome, an immune-related disorder caused by NOD2 gene mutations. It remains unclear in which population and to what extent next-generation sequencing techniques can aid in diagnosis. Methods We evaluated clinical usefulness of targeted next-generation sequencing in previously diagnosed JIA. Participants were required to have symptoms and signs suspected of Blau syndrome, including at least uveitis or cutaneous lesions in addition to arthritis. Targeted sequencing was conducted on NOD2 gene to detect diagnostic variants classified as pathogenic or likely pathogenic for Blau syndrome. We assessed the molecular diagnostic yield and clinical implications for patient care. Results Between 1 May 2008 and 1 June 2021, sequencing data were accrued from 123 previously diagnosed JIA (median age: 5 years; female: 62.6%). Targeted NOD2 sequencing yielded a positive molecular diagnosis of Blau syndrome in 21.1% (95% CI: 14.9%, 29.2%), encompassing six heterozygous missense mutations classified as pathogenic variants. Among those receiving a molecular diagnosis, changes in clinical management and treatment were considered as having occurred in 38.5%. Nine predictors were identified as being associated with a higher diagnostic yield, providing clinical clues to suspect the possibility of Blau syndrome. Conclusion Among some patients with paediatric-onset arthritis complicated with uveitis or cutaneous lesions, reassessment of the diagnosis of JIA may be warranted. Targeted NOD2 sequencing established the molecular diagnosis of Blau syndrome in nearly one-fifth of these cases and provided clinically relevant information for patient-care decisions. [ABSTRACT FROM AUTHOR]

Simple Summary: China's deer population is rich in resources and species; how to improve the health status of the deer population and reduce the occurrence of intestinal diseases is a necessary direction for current research. In this study, Enterococcus faecalis was used as the research object to explore the effect of lactic acid bacteria on deer growth performance and intestinal health and to further investigate the role played by lactic acid bacteria on the intestinal health status of deer. The results of this study showed that the addition of Enterococcus faecalis to the feed promoted weight gain, improved immune function, altered the structure of the intestinal flora of fallow deer, especially increasing the abundance of Firmicutes phylum, and increased the abundance of the Ruminococcaceae and Lacertococcaceae at the same phylum as that of Enterococcus faecalis. Furthermore, metabolomic analyses also revealed that Enterococcus faecalis supplementation increased the metabolism of lipids, carbohydrates and phospholipids by the intestinal microbiota. In conclusion, this study revealed the beneficial effects of lactic acid bacteria on growth traits, immunity and intestinal health of deer and provided a scientific basis for the further development of deer-specific probiotic products to promote intestinal health and reduce intestinal diseases in deer species in the future. Intestinal diseases are one of the diseases that affect the growth and immunity of deer. Currently, more lactic acid bacteria (LAB) are available as feed additives to improve the intestinal ecological balance of ruminants in production practices. In this study, Enterococcus faecalis was supplemented in the feed of fallow deer for 170 d, and body weights, blood indices and immune levels of fallow deer were counted at 35, 65 and 170 d. The effects of Enterococcus faecalis on the intestinal microbiota and the metabolism of fallow deer were analysed using 16S rDNA and UPLC-MS/MS methods. The results showed that the addition of Enterococcus faecalis to the diet improved body weight and immune function and increased the aggregation of gut microbiota in fallow deer. The addition of Enterococcus faecalis altered the community structure of intestinal microorganisms in fallow deer and increased the number of beneficial bacteria. In addition, combined with metabolomics analysis, it was found that supplementation with Enterococcus faecalis significantly altered the metabolites of fallow deer, mainly regulating lipid metabolism, carbohydrate metabolism and phospholipid metabolism. In conclusion, this study presents, for the first time, evidence that the LAB strain Enterococcus faecalis can be used as a potential probiotic for deer and points to a new direction for the treatment of intestinal disorders in the deer family. [ABSTRACT FROM AUTHOR]

In this Article, the sentence: "After 7 months of HFD, MUP-uPA mice developed HCC15, which contained numerous (usually 50-100 per tumour) non-recurrent coding mutations in pathways that are mutated in human HCC (Fig. 2d and Extended Data Fig. 6a).", should have read: "After 7 months of HFD, MUP-uPA mice developed HCC15, which contained numerous (usually 50-100 per tumour) non-recurrent mutations in pathways that are mutated in human HCC (Fig. 2d and Extended Data Fig. 6a).". This has been corrected online. In Extended Data Fig. 6a and b, which show the number of point mutations identified per sample and the mutational signatures, all sequence variants (including non-coding mutations) are shown. Fig. 2d also presents all variants compared to human mutations. In the Supplementary Information to this Amendment, we now provide the comparisons of all variants and coding variants to human mutations.

Dysregulated NLRP3 inflammasome activity results in uncontrolled inflammation, which underlies many chronic diseases. Although mitochondrial damage is needed for the assembly and activation of the NLRP3 inflammasome, it is unclear how macrophages are able to respond to structurally diverse inflammasome-activating stimuli. Here we show that the synthesis of mitochondrial DNA (mtDNA), induced after the engagement of Toll-like receptors, is crucial for NLRP3 signalling. Toll-like receptors signal via the MyD88 and TRIF adaptors to trigger IRF1-dependent transcription of CMPK2, a rate-limiting enzyme that supplies deoxyribonucleotides for mtDNA synthesis. CMPK2-dependent mtDNA synthesis is necessary for the production of oxidized mtDNA fragments after exposure to NLRP3 activators. Cytosolic oxidized mtDNA associates with the NLRP3 inflammasome complex and is required for its activation. The dependence on CMPK2 catalytic activity provides opportunities for more effective control of NLRP3 inflammasome-associated diseases.

This corrects the article DOI: 10.1038/nature24302.

The role of adaptive immunity in early cancer development is controversial. Here we show that chronic inflammation and fibrosis in humans and mice with non-alcoholic fatty liver disease is accompanied by accumulation of liver-resident immunoglobulin-A-producing (IgA+) cells. These cells also express programmed death ligand 1 (PD-L1) and interleukin-10, and directly suppress liver cytotoxic CD8+ T lymphocytes, which prevent emergence of hepatocellular carcinoma and express a limited repertoire of T-cell receptors against tumour-associated antigens. Whereas CD8+ T-cell ablation accelerates hepatocellular carcinoma, genetic or pharmacological interference with IgA+ cell generation attenuates liver carcinogenesis and induces cytotoxic T-lymphocyte-mediated regression of established hepatocellular carcinoma. These findings establish the importance of inflammation-induced suppression of cytotoxic CD8+ T-lymphocyte activation as a tumour-promoting mechanism.