Objectives
To evaluate the ability of geldanamycin to modulate two opposing TNFα/TNFR1-triggered signals for inflammation and cell death.
Methods
The effects of geldanamycin on TNFα-induced ...proinflammatory cytokine production, apoptosis, NF-κB activation, caspase activation, and necroptosis in a human rheumatoid synovial cell line (MH7A) were evaluated via ELISA/qPCR, flow cytometry, dual-luciferase reporter assay, and western blotting assay, respectively. In addition, therapeutic effects on murine collagen-induced arthritis (CIA) were also evaluated.
Results
Geldanamycin disrupted RIPK1 in MH7A, thereby inhibiting TNFα-induced proinflammatory cytokine production and enhancing apoptosis. TNFα-induced NF-κB and MLKL activation was inhibited, whereas caspase 8 activation was enhanced. Recombinant RIPK1 restored the geldanamycin-mediated inhibition of TNFα-induced NF-κB activation. In addition, GM showed more clinical effectiveness than a conventional biologic TNF inhibitor, etanercept, in murine CIA and significantly attenuated synovial hyperplasia, a histopathological hallmark of RA.
Conclusions
GM disrupts RIPK1 and selectively inhibits the TNFR1-triggered NF-κB activation signaling pathway, while enhancing the apoptosis signaling pathway upon TNFα stimulation, thereby redressing the balance between these two opposing signals in a human rheumatoid synovial cell line. Therapeutic targeting RIPK1 may be a novel concept which involves TNF inhibitor acting as a TNFR1-signal modulator and have great potential for a more fundamental, effective, and safer TNF inhibitor.
Key Points
• Geldanamycin (GM) disrupts RIPK1 and selectively inhibits the TNFR1-triggered NF-κB activation signaling pathway while enhancing the apoptosis signaling pathway upon TNFα stimulation, thereby redressing the balance between these two opposing signals in a human rheumatoid synovial cell line, MH7A.
• GM showed more clinical effectiveness than a conventional biologic TNF-inhibitor, etanercept, in murine collagen-induced arthritis (CIA), and significantly attenuated synovial hyperplasia, a histopathological hallmark of RA.
• Therapeutic targeting RIPK1 may be a novel concept which involves TNF inhibitor acting as a TNFR1-signal modulator and have great potential for a more fundamental, effective, and safer TNF-inhibitor.
Alteration of the gut microbiome has been linked to the pathogenesis of systemic lupus erythematosus (SLE). However, a comprehensive view of the gut microbiome in SLE and its interaction with the ...host remains to be revealed. This study aimed to reveal SLE-associated changes in the gut microbiome and its interaction with the host by a comprehensive metagenome-wide association study (MWAS) followed by integrative analysis.
We performed a MWAS of SLE based on shotgun sequencing of the gut microbial DNA from Japanese individuals (
=47,
=203). We integrated the result of the MWAS with the genome-wide association study (GWAS) data and plasma metabolite data.
Via species level phylogenetic analysis, we identified and validated increases of
and
in the patients with SLE. Microbial gene analysis revealed increases of
-derived genes including one involved in redox reaction. Additionally, microbial pathways related to sulfur metabolism and flagella assembly were altered in the patients with SLE. We identified an overlap in the enriched biological pathways between the metagenome and the germline genome by comparing the result of the MWAS and the GWAS of SLE (ie, MWAS-GWAS interaction). α-diversity and β-diversity analyses provided evidence of dysbiosis in the metagenome of the patients with SLE. Microbiome-metabolome association analysis identified positive dosage correlation of acylcarnitine with
, an SLE-associated taxon.
Our MWAS followed by integrative analysis revealed SLE-associated changes in the gut microbiome and its interaction with the host, which contribute to our understanding of the relationship between the microbiome and SLE.
The relationship between autoimmune diseases and the gut microbiome has been intensively studied, and several autoimmunity-associated bacterial taxa have been identified. However, much less is known ...about the roles of the gut virome in autoimmune diseases.
Here, we performed a whole gut virome analysis based on the shotgun sequencing of 476 Japanese which included patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis and healthy control subjects.
Our case-control comparison of the viral abundance revealed that crAss-like phages, which are one of the main components of a healthy gut virome, significantly decreased in the gut of the patients with autoimmune disease, specifically the patients with RA and SLE. In addition,
significantly decreased in the gut of the patients with SLE. To understand how these viruses affected the bacteriome, we performed a quantitative virus-bacterium association analysis and clustered regularly interspaced short palindromic repeat-based virus-bacterium interaction analysis. We identified a symbiosis between
e and
. In addition, multiple bacterial targets of crAss-like phages were identified (eg,
spp).
Our data suggest that the gut virome can affect our body either directly or via bacteria. Our analyses have elucidated a previously missing part of the autoimmunity-associated gut microbiome and presented new candidates that contribute to the development of autoimmune diseases.
The impact of SARS-CoV-2 infection on the gut fungal (mycobiota) and bacterial (microbiota) communities has been elucidated individually. This study analyzed both gut mycobiota and microbiota and ...their correlation in the COVID-19 patients with severe and mild conditions and follow-up to monitor their alterations after recovery. We analyzed the gut mycobiota and microbiota by bacterial 16S and fungal ITS1 metagenomic sequencing of 40 severe patients, 38 mild patients, and 30 healthy individuals and reanalyzed those of 10 patients with severe COVID-19 approximately 6 months after discharge. The mycobiota of the severe and mild groups showed lower diversity than the healthy group, and in some, characteristic patterns dominated by a single fungal species, Candida albicans, were detected. Lower microbial diversity in the severe group was observed, but no differences in its diversity or community structure were detected between the mild and healthy groups. The microbiota of the severe group was characterized by an increase in Enterococcus and Lactobacillus, and a decrease in Faecalibacterium and Bacteroides. The abundance of Candida was positively correlated with that of Enterococcus in patients with COVID-19. After the recovery of severe patients, alteration of the microbiota remained, but the mycobiota recovered its diversity comparable to that of mild and healthy groups. In mild cases, the microbiota is stable during SARS-CoV-2 infection, but in severe cases, alterations persist for 6 months after recovery.
Interaction between the gut microbiome and host plays a key role in human health. Here, we perform a metagenome shotgun-sequencing-based analysis of Japanese participants to reveal associations ...between the gut microbiome, host genetics, and plasma metabolome. A genome-wide association study (GWAS) for microbial species (n = 524) identifies associations between the PDE1C gene locus and Bacteroides intestinalis and between TGIF2 and TGIF2-RAB5IF gene loci and Bacteroides acidifiaciens. In a microbial gene ortholog GWAS, agaE and agaS, which are related to the metabolism of carbohydrates forming the blood group A antigen, are associated with blood group A in a manner depending on the secretor status determined by the East Asian-specific FUT2 variant. A microbiome-metabolome association analysis (n = 261) identifies associations between bile acids and microbial features such as bile acid metabolism gene orthologs including bai and 7β-hydroxysteroid dehydrogenase. Our publicly available data will be a useful resource for understanding gut microbiome-host interactions in an underrepresented population.
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•Construction of Japanese multi-omics datasets (gut microbiome, plasma metabolome, host genome)•Genome-wide association analysis of the gut microbiome with 524 Japanese individuals•ABO blood type was associated with the microbial genes related to N-galactosamine metabolism•Microbiome-metabolome association analysis highlights the association involving bile acids
Tomofuji et al. constructed Japanese multi-omics datasets (gut microbiome, plasma metabolome, and host genome). Their shotgun-sequencing-based gut microbiome analysis identified associations with the host genome and plasma metabolome including those involving microbial genes. Multi-omics analysis in the underrepresented population would contribute to expanding the diversity of the studied populations.
To report anterior chamber flare using laser flare photometry and ciliochoroidal detachment using anterior segment optical coherence tomography (AS-OCT) in a new onset acute lupus choroidopathy case.
...A 57-year-old woman with severe nephritis, pleural effusion, and ascites was referred to our ophthalmology clinic for rapid onset of bilateral blurred vision and eyelid swelling. She had a bilateral high-flared, shallow anterior chamber, and bilateral ciliochoroidal detachment, which was revealed using laser flare photometry and AS-OCT. She also had a serous retinal detachment and disc-macular retinoschisis with a thicker choroid and waved Bruch's membrane. Indocyanine green angiography (ICGA) demonstrated partial hypocyanescence in the early phase and multiple hypercyanescent spots at the intermediate to late phase, which are typical of lupus choroidopathy. Systemic lupus erythematosus was diagnosed, and after the administration of pulse methylprednisolone and pulse cyclophosphamide therapies, all eye findings completely resolved in a month, and all other signs and symptoms improved.
Lupus choroidopathy, which is less common than retinopathy, might be under-diagnosed because of its difficult evaluation. Although ICGA is the gold standard for diagnosing lupus choroidopathy, a high flare of the anterior chamber and ciliochoroidal detachment might be different from lupus retinopathy. Laser flare photometry and AS-OCT can be non-invasive, helpful tools for the longitudinal evaluation of the patient's response to therapy.
is considered to be a contributing factor in rheumatoid arthritis (RA). However, in some non-Westernised countries, healthy individuals also harbour an abundance of
in the intestine. This study ...investigated the pathogenicity of RA patient-derived
(
) compared with healthy control-derived
(
).
We obtained 13
.
strains from the faeces of patients with RA and healthy controls. Following whole genome sequencing, the sequences of
and
were compared. To analyse the arthritis-inducing ability of
, we examined two arthritis models (1) a collagen-induced arthritis model harbouring
under specific-pathogen-free conditions and (2) an SKG mouse arthritis model under
-monocolonised conditions. Finally, to evaluate the ability of
to activate innate immune cells, we performed in vitro stimulation of bone marrow-derived dendritic cells (BMDCs) by
and
.
Comparative genomic analysis revealed no apparent differences in the core gene contents between
and
, but pangenome analysis revealed the high genome plasticity of
. We identified a
-specific genomic region as a conjugative transposon. In both arthritis models,
-induced more severe arthritis than
. In vitro BMDC stimulation experiments revealed the upregulation of IL-17 and Th17-related cytokines (IL-6, IL-23) by
.
Our findings reveal the genetic diversity of
, and the genomic signatures associated with strong arthritis-inducing ability of
. Our study contributes towards elucidation of the complex pathogenesis of RA.
T cells differentiate into highly diverse subsets and display plasticity depending on the environment. Although lymphocytes are key mediators of inflammation, functional specialization of T cells in ...inflammatory bowel disease (IBD) has not been effectively described. Here, we performed deep profiling of T cells in the intestinal mucosa of IBD and identified a CD4
tissue-resident memory T cell (Trm) subset that is increased in Crohn's disease (CD) showing unique inflammatory properties. Functionally and transcriptionally distinct CD4
Trm subsets are observed in the inflamed gut mucosa, among which a CD-specific CD4
Trm subset, expressing CD161 and CCR5 along with CD103, displays previously unrecognized pleiotropic signatures of innate and effector activities. These inflammatory features are further enhanced by their spatial proximity to gut epithelial cells. Furthermore, the CD-specific CD4
Trm subset is the most predominant producer of type 1 inflammatory cytokines upon various stimulations among all CD4
T cells, suggesting that the accumulation of this T cell subset is a pathological hallmark of CD. Our results provide comprehensive insights into the pathogenesis of IBD, paving the way for decoding of the molecular mechanisms underlying this disease.
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