Featured
-
-
Article
| Open AccessLupus enhancer risk variant causes dysregulation of IRF8 through cooperative lncRNA and DNA methylation machinery
The functional effects of genetic loci associated with autoimmune disease are not well understood. By dissecting an autoimmune disease genetic locus, the authors define an immune cell-type-specific enhancer and the molecular mechanisms underlying the dysregulation of IRF8 expression by lupus risk variants.
- Tian Zhou
- , Xinyi Zhu
- & Nan Shen
-
Article
| Open AccessSelenophosphate synthetase 1 deficiency exacerbates osteoarthritis by dysregulating redox homeostasis
Osteoarthritis is caused by the gradual accumulation of oxidative stress in cartilage. Here, the authors show that dysregulation of the selenium metabolic pathway underlies a shift in redox homeostasis in chondrocytes, leading to chronic osteoarthritic changes in joints.
- Donghyun Kang
- , Jeeyeon Lee
- & Jin-Hong Kim
-
Article
| Open AccessTNF antagonist sensitizes synovial fibroblasts to ferroptotic cell death in collagen-induced arthritis mouse models
Expansion of synovial fibroblast is associated with rheumatoid arthritis (RA) progression, but how this expansion is regulated is still not clear. Here the authors use a mouse RA model, single cell RNA sequencing and in vitro analyses to show that inducing ferroptosis and suppressing TNF signaling reduce fibroblast numbers and ameliorate experimental arthritis.
- Jiao Wu
- , Zhuan Feng
- & Ping Zhu
-
Article
| Open AccessAdenosine receptor 2a agonists target mouse CD11c+T-bet+ B cells in infection and autoimmunity
CD11c+T-bet+ B cells have been linked with different autoimmune diseases, but targeting these cells has been challenging. Here the authors use an adenosine 2A receptor agonist to deplete these B cells and to inhibit or reverse autoimmune symptoms and pathology in mice.
- Russell C. Levack
- , Krista L. Newell
- & Gary M. Winslow
-
Article
| Open AccessMacrophages in epididymal adipose tissue secrete osteopontin to regulate bone homeostasis
Visceral adipose tissue secretes cytokines to regulate the homeostasis of organs. Here, the authors show that epididymal white adipose tissue-secreted osteopontin induces lipophagocytic mobilization of macrophages and promotes bone matrix degradation via activating osteoclasts.
- Bingyang Dai
- , Jiankun Xu
- & Ling Qin
-
Article
| Open AccessTargeting necroptosis in muscle fibers ameliorates inflammatory myopathies
Polymyositis (PM) is a chronic inflammatory myopathy characterized by progressive muscle weakness. Here the authors showed that muscle fibers in PM undergo necroptosis and aggravate inflammation via releasing pro-inflammatory molecules such as HMGB1.
- Mari Kamiya
- , Fumitaka Mizoguchi
- & Shinsuke Yasuda
-
Article
| Open AccessMechanical force promotes dimethylarginine dimethylaminohydrolase 1-mediated hydrolysis of the metabolite asymmetric dimethylarginine to enhance bone formation
Mechanical force is critical for the development and remodeling of bones. Here the authors report that mechanical force regulates the production of the metabolite asymmetric dimethylarginine via regulating the expression of the hydrolytic enzyme dimethylarginine dimethylaminohydrolase 1 in osteoblasts.
- Ziang Xie
- , Lei Hou
- & Shunwu Fan
-
Article
| Open AccessProteomic profiling of MIS-C patients indicates heterogeneity relating to interferon gamma dysregulation and vascular endothelial dysfunction
Multi-inflammatory syndrome in children (MIS-C) can be associated with SARS-CoV-2 infection but can also be similar to other inflammatory syndromes. Here the authors characterise the plasma proteome phenotype in MIS-C and compare to other SARS-CoV-2 related syndromes and find disproportionately high IFN-γ responses in MIS-C patients.
- Caroline Diorio
- , Rawan Shraim
- & Edward M. Behrens
-
Article
| Open AccessTargeting chondrocytes for arresting bony fusion in ankylosing spondylitis
Current treatments cannot significantly alleviate the radiographic progression in ankylosing spondylitis (AS), which results in joints stiffness and bony fusion of AS. Smo inhibitor sonidegib retards the pathological new bone formation in AS through targeting dysfunctional chondrogenesis.
- Fenli Shao
- , Qianqian Liu
- & Yang Sun
-
Article
| Open AccessDamaged brain accelerates bone healing by releasing small extracellular vesicles that target osteoprogenitors
Concomitant traumatic brain injury accelerates bone healing, but the mechanism is unclear. Here, the authors show that injured neurons, mainly those in the hippocampus, release osteogenic miRNA-enriched small extracellular vesicles, which targete osteoprogenitors to stimulate bone formation.
- Wei Xia
- , Jing Xie
- & Xiaochun Bai
-
Article
| Open AccessInterleukin-31 promotes fibrosis and T helper 2 polarization in systemic sclerosis
Systemic sclerosis (SSc) disease involves multisystem fibrosis and autoimmunity with limited treatment options. Here the authors demonstrate that IL-31 and IL-31RA are overexpressed in dermal fibroblasts from SSc patients and show that fibrosis and cytokine release can be reduced upon blocking of IL-31/IL-31RA.
- Ai Kuzumi
- , Ayumi Yoshizaki
- & Shinichi Sato
-
Article
| Open AccessAutomated bone mineral density prediction and fracture risk assessment using plain radiographs via deep learning
Dual-energy X-ray absorptiometry and the Fracture Risk Assessment Tool are recommended tools for osteoporotic fracture risk evaluation, but are underutilized. Here, the authors present an opportunistic tool to identify fractures, predict bone mineral density and evaluate fracture risk using plain pelvis and lumbar spine radiographs.
- Chen-I Hsieh
- , Kang Zheng
- & Chang-Fu Kuo
-
Article
| Open AccessTNF-α-mediated m6A modification of ELMO1 triggers directional migration of mesenchymal stem cell in ankylosing spondylitis
Abnormal functions of mesenchymal stem cells (MSC) contribute into the pathogenensis of ankylosing spondylitis (AS). Here, the authors show that TNF-α at high concentration induces enhances migration of AS-MSC through METTL14 mediated m6A modification of the ELMO1 3′ UTR.
- Zhongyu Xie
- , Wenhui Yu
- & Huiyong Shen
-
Article
| Open AccessLong-term treatment with senolytic drugs Dasatinib and Quercetin ameliorates age-dependent intervertebral disc degeneration in mice
Intervertebral disc degeneration is a leading cause of chronic back pain and disability. Here the authors show that long term treatment with senolytic compounds Dasatinib and Quercetin reduces disc senescence burden and ameliorates age-dependent degeneration in mice.
- Emanuel J. Novais
- , Victoria A. Tran
- & Makarand V. Risbud
-
Article
| Open AccessNGF-TrkA signaling dictates neural ingrowth and aberrant osteochondral differentiation after soft tissue trauma
Soft tissue trauma can result in aberrant osteochondral differentiation of local mesenchymal progenitor cells. Here the authors show that, in mice, soft tissue trauma results in NGF expression by perivascular cells, which leads to axonal invasion and drives abnormal osteochondral differentiation, and show that this process can be prevented by inhibition of NGF signaling.
- Seungyong Lee
- , Charles Hwang
- & Benjamin Levi
-
Article
| Open AccessRSPO3 is important for trabecular bone and fracture risk in mice and humans
Genetic association signals for fractures have been reported at the RSPO3 locus, but the causal gene and the underlying mechanism are unknown. Here, the authors show that RSPO3 exerts an important role for vertebral trabecular bone mass and bone strength in mice and fracture risk in humans.
- Karin H. Nilsson
- , Petra Henning
- & Claes Ohlsson
-
Article
| Open AccessOncogene-induced senescence in hematopoietic progenitors features myeloid restricted hematopoiesis, chronic inflammation and histiocytosis
BRAF-MAPK activating mutations are reported in histiocytoses—hematological neoplasms with widespread pro-inflammatory myeloid cells. Here, the authors show that an activating mutant BRAF in haematopoietic stem and progenitor cells causes an oncogene-induced senescence response leading to myeloid restricted haematopoiesis, inflammation and histiocytosis.
- Riccardo Biavasco
- , Emanuele Lettera
- & Eugenio Montini
-
Article
| Open AccessTGFβ promotes fibrosis by MYST1-dependent epigenetic regulation of autophagy
Uncontrolled activation of fibroblasts contributes to tissue fibrosis and organ dysfunction. Here the authors demonstrate that the epigenetic control of autophagy is disturbed by a TGFβ-dependent downregulation of MYST1 in systemic sclerosis patients. Restoration of the epigenetic control of autophagy reduces fibroblast activation and ameliorates fibrotic tissue remodeling.
- Ariella Zehender
- , Yi-Nan Li
- & Jörg H. W. Distler
-
Article
| Open AccessMyofibroblast transcriptome indicates SFRP2hi fibroblast progenitors in systemic sclerosis skin
Myofibroblasts drive fibrosis in systemic sclerosis (SSc), but the cellular progenitors are unknown. Utilizing single cell RNA-sequencing, the authors show that SSc dermal myofibroblasts arise in a two-step process from SFRP2/DPP4-expressing progenitors and implicate upstream transcription factors.
- Tracy Tabib
- , Mengqi Huang
- & Robert Lafyatis
-
Article
| Open AccessLasp1 regulates adherens junction dynamics and fibroblast transformation in destructive arthritis
Fibroblast-like synoviocytes are important mediators of joint pathology in rheumatoid arthritis (RA). Here the authors show that Lasp1 is epigenetically regulated and highly expressed by these cells in RA and its deletion can limit joint pathology in a mouse model of inflammatory arthritis.
- Denise Beckmann
- , Anja Römer-Hillmann
- & Adelheid Korb-Pap
-
Article
| Open AccessA new molecular classification to drive precision treatment strategies in primary Sjögren’s syndrome
Sjögren’s syndrome, a disease that primarily affects women, is poorly understood. Here, the authors combine data from a large cohort of patients and healthy controls to identify biomarkers that distinguish patient subgroups to improve our understanding of the disease and facilitate drug development.
- Perrine Soret
- , Christelle Le Dantec
- & Jacques-Olivier Pers
-
Article
| Open AccessPhase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus
Increased risk of premature cardiovascular disease in systemic lupus erythematosus (SLE) is not well understood, but in animal models, the Janus kinase inhibitor tofacitinib improves related phenotypes. Here the authors report a Phase 1 double-blind randomized trial that shows tofacitinib is safe and well tolerated in in patients with SLE.
- Sarfaraz A. Hasni
- , Sarthak Gupta
- & Mariana J. Kaplan
-
Article
| Open AccessConserved human effector Treg cell transcriptomic and epigenetic signature in arthritic joint inflammation
T regulatory (Treg) cells can differentiate into effector Treg (eTreg) cells that might be functional in inflammatory diseases. Using RNA sequencing and epigenetic profiling, the authors show that eTreg signatures in juvenile idiopathic arthritis joints are similar to tumour microenvironment (TME) Treg cells and are affected by tissue-specific epigenetic regulation.
- Gerdien Mijnheer
- , Lisanne Lutter
- & Femke van Wijk
-
Article
| Open AccessLoss of α2-6 sialylation promotes the transformation of synovial fibroblasts into a pro-inflammatory phenotype in arthritis
Dysregulation of synovial fibroblasts is thought to be an important step in the pathogenesis of rheumatoid arthritis. Here the authors implicate α2-6 sialylation in this process by studying the glycome of these cells in patients and in a mouse model of inflammatory joint disease.
- Yilin Wang
- , Aneesah Khan
- & Miguel A. Pineda
-
Article
| Open AccessTargeted apoptosis of macrophages and osteoclasts in arthritic joints is effective against advanced inflammatory arthritis
Celastrol might be useful in treating rheumatoid arthritis in part by inhibiting apoptosis of macrophages; however, systemic toxicity is a concern. Here the authors design celastrol-loaded nanoparticles that release a payload in response to MMP9 cleavage and show these NPs are effective at inducing apoptosis of human macrophages in vitro and a therapeutic effect with an adjuvant-induced arthritis model in rats.
- Caifeng Deng
- , Quan Zhang
- & Zhirong Zhang
-
Article
| Open AccessType I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus
Lupus pathogenesis is associated with high type 1 interferon stimulated gene (ISG) expression. Here, the authors correlate ISG expression in CD8+ T cells from lupus nephritis patients with abnormal mitochondrial function, implicating increased NAD consumption and reduced cell viability in the pathogenesis.
- Norzawani Buang
- , Lunnathaya Tapeng
- & Marina Botto
-
Article
| Open AccessA scalable physician-level deep learning algorithm detects universal trauma on pelvic radiographs
Pelvic radiographs (PXRs) are essential for detecting proximal femur and pelvis injuries in trauma patients, but none of the currently available algorithms can detect all kinds of trauma-related radiographic findings. Here, the authors develop a multiscale deep learning algorithm trained with weakly supervised point annotation.
- Chi-Tung Cheng
- , Yirui Wang
- & Le Lu
-
Article
| Open AccessArachidonic acid-regulated calcium signaling in T cells from patients with rheumatoid arthritis promotes synovial inflammation
ORAI3 is part of pore forming calcium channels involved in T cell activation. Here the authors show that there is increased expression of ORAI3 in T cells from patients with rheumatoid arthritis and that the transcription factor IKAROS negatively regulates the ORAI3 promoter, indicating a regulatory loop that can control auto-reactivity of T cells in these patients.
- Zhongde Ye
- , Yi Shen
- & Jörg J. Goronzy
-
Article
| Open AccessIdentification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups
The presentation of systemic lupus erythematosus has been known to differ by ancestry, but the underlying genetic factors remain unclear. Here, the authors report ancestry-specific susceptibility loci and better risk prediction when using data from matched ancestral groups.
- Yong-Fei Wang
- , Yan Zhang
- & Wanling Yang
-
Article
| Open AccessAccelerating functional gene discovery in osteoarthritis
Osteoarthritis is a chronic, heritable disease with no available treatment. Here, the authors show that a validated, rapid-throughput joint phenotyping pipeline detects osteoarthritis in the mouse knee following surgical provocation, in aging and after single gene deletion or point mutation.
- Natalie C. Butterfield
- , Katherine F. Curry
- & J. H. Duncan Bassett
-
Article
| Open AccessSingle cell transcriptomic analysis of human pluripotent stem cell chondrogenesis
Application of human induced pluripotent stem cells (hiPSCs) for tissue regeneration is hindered by off-target cell differentiation. Here, the authors use bulk and single cell RNA-sequencing to identify WNT and MITF as off-target hubs during chondrogenic differentiation; inhibiting these pathways enhanced homogeneity and yield.
- Chia-Lung Wu
- , Amanda Dicks
- & Farshid Guilak
-
Article
| Open AccessFunctionally impaired plasmacytoid dendritic cells and non-haematopoietic sources of type I interferon characterize human autoimmunity
Type I interferon drives autoimmune pathology in SLE and has been assumed to come predominantly from plasmacytoid dendritic cells (pDCs). Here, the authors show that prior to the onset of SLE, pDCs lose multiple immunogenic functions and, instead, non-hematopoietic cells such as keratinocytes are a major source of type I interferons.
- Antonios Psarras
- , Adewonuola Alase
- & Edward M. Vital
-
Article
| Open AccessChromatin accessibility landscapes of skin cells in systemic sclerosis nominate dendritic cells in disease pathogenesis
Systemic sclerosis (SSc) is a disease with manifestation in the skin and immune etiology, but the pathogenic immune cell types remain unidentified. Here the authors use ATAC-seq to profile chromatin landscapes of skin samples from patients with SSc to implicate skin dendritic cells for having the strongest disease-associated epigenetic changes.
- Qian Liu
- , Lisa C. Zaba
- & Howard Y. Chang
-
Article
| Open AccessBlood pro-resolving mediators are linked with synovial pathology and are predictive of DMARD responsiveness in rheumatoid arthritis
Being able to predict the therapeutic benefit of disease modifying anti-rheumatic drugs (DMARDs) would be of great benefit and a stepping stone towards personalized medicine. Here the authors use machine learning and lipid mediator mass spectrometry to show specialized pro-resolving mediators are indicative of DMARD responsiveness among rheumatoid arthritis patients.
- Esteban A. Gomez
- , Romain A. Colas
- & Jesmond Dalli
-
Article
| Open AccessCalcium-sensing receptor-mediated NLRP3 inflammasome response to calciprotein particles drives inflammation in rheumatoid arthritis
How extracellular calcium can trigger Nlrp3 inflammasome activation has been somewhat controversial and unclear. Here the authors show calciprotein particles are taken up by myeloid cells via calcium-sensing receptor-dependent macropinocytosis in response to high levels of extracellular Ca2+ and this pathway might be critical to inflammatory conditions.
- Elisabeth Jäger
- , Supriya Murthy
- & Ulf Wagner
-
Article
| Open AccessPatients with immune-mediated inflammatory diseases receiving cytokine inhibitors have low prevalence of SARS-CoV-2 seroconversion
Cytokine storm seems to be a common feature of severe COVID-19 pathology. Here, the authors show a reduced rate of SARS-CoV2 positivity in a large population of patients with immune-mediated inflammatory diseases if they are already being treated with cytokine or JAK inhibitors, indicating these treatments are safe to continue and are possibly protective against COVID19.
- David Simon
- , Koray Tascilar
- & Georg Schett
-
Article
| Open AccessLDHA-mediated ROS generation in chondrocytes is a potential therapeutic target for osteoarthritis
Chondrocytes have altered cellular metabolism in the context of osteoarthritis, but whether and how these changes are associated with inflammation is a controversial area. Here the authors show that inflammatory NF-κB signalling drives a glycolytic shift in chondrocytes and the production of ROS, which drives cartilage catabolism.
- Manoj Arra
- , Gaurav Swarnkar
- & Yousef Abu-Amer
-
Article
| Open AccessTargeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis
Intestinal dysbiosis is associated with an ever-growing list of autoimmune diseases. Here the authors show that both mice and humans with autoimmune arthritis can have dysbiosis and barrier leakiness prior to major signs of inflammatory arthritis, and treatment of mice with a zonulin antagonist can limit collagen-induced arthritis.
- Narges Tajik
- , Michael Frech
- & Mario M. Zaiss
-
Article
| Open AccessEthanol consumption inhibits TFH cell responses and the development of autoimmune arthritis
Moderate consumption of alcohol is associated with protection from some autoimmune diseases. Here the authors show that ethanol and its metabolite acetate can protect mice from collagen-induced arthritis and provide evidence that the mechanism of this effect might be via inhibition of the effector function of T follicular helper cells.
- Vugar Azizov
- , Katharina Dietel
- & Mario M. Zaiss
-
Article
| Open AccessScavenger receptor-A is a biomarker and effector of rheumatoid arthritis: A large-scale multicenter study
Scavenger receptor-A (SR-A) is mostly expressed by myeloid cells and has been attributed a variety of biological functions. Here the authors assess SR-A as a biomarker for diagnosis of rheumatoid arthritis (RA) using large-scale training and validation cohorts and show that modulating SR-A levels can alter progression of collagen-induced arthritis in mice.
- Fanlei Hu
- , Xiang Jiang
- & Zhanguo Li
-
Article
| Open AccessLupus autoantibodies act as positive allosteric modulators at GluN2A-containing NMDA receptors and impair spatial memory
Systemic lupus erythematosus (SLE) is an autoimmune disorder which can have neurological manifestations, including autoantibody targeting of the NMDA receptor. In this study, the authors GluN2A subunit is a target of SLE autoantibodies, using sample derived from patient.
- Kelvin Chan
- , Jacquelyn Nestor
- & Lonnie P. Wollmuth
-
Article
| Open AccessTherapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution of arthritis
Fibroblast hyper-activation and proliferation is a major feature in arthritis, yet scarcely addressed for anti-arthritic therapies. Here, the authors show that activation of the MC1 receptor induces fibroblast senescence associated with a reparative phenotype, ultimately regulating experimental inflammatory arthritis.
- Trinidad Montero-Melendez
- , Ai Nagano
- & Mauro Perretti
-
Article
| Open AccessEnvironmental arginine controls multinuclear giant cell metabolism and formation
Multinucleated giant cells (MGCs) are important in the pathogenesis of various diseases. Here, the authors demonstrate that extracellular presence of the amino acid arginine is required for MGC formation and metabolism, suggesting a translational impact for strategies utilizing systemic arginine depletion in MGC-mediated diseases.
- Julia S. Brunner
- , Loan Vulliard
- & Gernot Schabbauer
-
Article
| Open AccessGM-CSF drives dysregulated hematopoietic stem cell activity and pathogenic extramedullary myelopoiesis in experimental spondyloarthritis
Spondyloarthritis pathology is manifested by increased myeloid infiltration of the joints. Here the authors show that in a mouse model of spondyloarthritis, a single dose of a microbial ligand curdlan induces persistent extramedullary myelopoiesis in the spleen and joints, which is driven by GM-CSF and can be amplified by exogenous IL-33.
- Daniel Regan-Komito
- , James W. Swann
- & Thibault Griseri
-
Article
| Open AccessIgA subclasses have different effector functions associated with distinct glycosylation profiles
Immunoglobulin A (IgA) has two subclasses, IgA1 and IgA2, but differential effects on inflammation are unclear. Here the authors show that IgA2, when compared with IgA1, has stronger pro-inflammatory functions associated with changed glycosylation and higher disease scores in patients with rheumatoid arthritis.
- Ulrike Steffen
- , Carolien A. Koeleman
- & Georg Schett
-
Article
| Open AccessHeritability of skewed X-inactivation in female twins is tissue-specific and associated with age
Skewing of X chromosome inactivation (XCI) occurs when the silencing of one parental X chromosome is non-random. Here, Zito et al. report XCI patterns in lymphoblastoid cell lines, blood, subcutaneous adipose tissue samples and skin samples of monozygotic and dizygotic twins and find XCI skew to associate with tissue and age.
- Antonino Zito
- , Matthew N. Davies
- & Kerrin S. Small
-
Article
| Open AccessGenome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status
Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disorder characterised by asthma, eosinophilia and vasculitis. Here, the authors describe a genome-wide association study of EGPA that reveals clinical and genetic differences between subgroups stratified by autoantibody status (ANCA).
- Paul A Lyons
- , James E Peters
- & Kenneth G. C. Smith
-
Article
| Open AccessGWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways
Systemic sclerosis (SSc) is a heterogeneous chronic autoimmune disease that affects the connective tissue. Here, López-Isac et al. identify 13 new risk loci for SSc as well as loci specific for limited cutaneous and diffuse SSc and, defining credible sets and performing functional annotation, highlight key pathways and cell types for SSc.
- Elena López-Isac
- , Marialbert Acosta-Herrera
- & Javier Martin
-
Article
| Open AccessIntestinal microbiome composition and its relation to joint pain and inflammation
Alterations to the microbiome are now associated with various diseases. Here the authors analyze microbiomes from a large population based cohort and show positive correlations between abundance of Streptococcus spp. and osteoarthritis-related knee pain.
- Cindy G. Boer
- , Djawad Radjabzadeh
- & Joyce B. J. van Meurs