Driving chronicity in rheumatoid arthritis: perpetuating role of myeloid cells

Alivernini, Stefano; Tolusso, Barbara; Ferraccioli, Gianfranco; Gremese, Elisa; Kurowska‐Stolarska, Mariola; McInnes, Iain B.

doi:10.1111/cei.13098

Cited by 36 publications

(25 citation statements)

References 115 publications

(148 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The molecular mechanisms resulting in non-resolving inflammation in the context of RA remain obscure 5 9 10. An inflammatory response typically follows a multistep evolution from induction to resolution aiming to finally restore the function and structure of the affected tissues 11 12.…”

Section: Introductionmentioning

confidence: 99%

TNF-induced inflammatory genes escape repression in fibroblast-like synoviocytes: transcriptomic and epigenomic analysis

et al. 2019

View full text Add to dashboard Cite

ObjectiveWe investigated genome-wide changes in gene expression and chromatin remodelling induced by tumour necrosis factor (TNF) in fibroblast-like synoviocytes (FLS) and macrophages to better understand the contribution of FLS to the pathogenesis of rheumatoid arthritis (RA).MethodsFLS were purified from patients with RA and CD14+ human monocyte-derived macrophages were obtained from healthy donors. RNA-sequencing, histone 3 lysine 27 acetylation (H3K27ac), chromatin immunoprecipitation-sequencing (ChIP-seq) and assay for transposable accessible chromatin by high throughput sequencing (ATAC-seq) were performed in control and TNF-stimulated cells.ResultsWe discovered 280 TNF-inducible arthritogenic genes which are transiently expressed and subsequently repressed in macrophages, but in RA, FLS are expressed with prolonged kinetics that parallel the unremitting kinetics of RA synovitis. 80 out of these 280 fibroblast-sustained genes (FSGs) that escape repression in FLS relative to macrophages were desensitised (tolerised) in macrophages. Epigenomic analysis revealed persistent H3K27 acetylation and increased chromatin accessibility in regulatory elements associated with FSGs in TNF-stimulated FLS. The accessible regulatory elements of FSGs were enriched in binding motifs for nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), interferon-regulatory factors (IRFs) and activating protein-1 (AP-1). Inhibition of bromodomain and extra-terminal motif (BET) proteins, which interact with histone acetylation, suppressed sustained induction of FSGs by TNF.ConclusionOur genome-wide analysis has identified the escape of genes from transcriptional repression in FLS as a novel mechanism potentially contributing to the chronic unremitting synovitis observed in RA. Our finding that TNF induces sustained chromatin activation in regulatory elements of the genes that escape repression in RA FLS suggests that altering or targeting chromatin states in FLS (eg, with inhibitors of BET proteins) is an attractive therapeutic strategy.

show abstract

Section: Introductionmentioning

confidence: 99%

TNF-induced inflammatory genes escape repression in fibroblast-like synoviocytes: transcriptomic and epigenomic analysis

et al. 2019

View full text Add to dashboard Cite

show abstract

“…The stimulation of these receptors produces the expression of proinflammatory cytokines such as tumor necrosis factor (TNF) α , interleukin- (IL-) 6, IL-1 β , or IL-12 by several innate cells such as dendritic cells (DCs) or macrophages, which link innate and adaptive immunity. Inflammation in RA patients is maintained by sustained activation of multiple inflammatory positive-feedback regulatory pathways in a variety of cells [ 12 ]. As a consequence of all these processes that have been unleashed in early RA, there is an alteration in the balance between the different subpopulations of Th lymphocytes.…”

Section: An Introduction To the Physiopathology Of Rheumatoid Arthmentioning

confidence: 99%

The Anti-Inflammatory Mediator, Vasoactive Intestinal Peptide, Modulates the Differentiation and Function of Th Subsets in Rheumatoid Arthritis

Villanueva‐Romero

Gutiérrez‐Cañas

Carrión

et al. 2018

Journal of Immunology Research

View full text Add to dashboard Cite

Genetic background, epigenetic modifications, and environmental factors trigger autoimmune response in rheumatoid arthritis (RA). Several pathogenic infections have been related to the onset of RA and may cause an inadequate immunological tolerance towards critical self-antigens leading to chronic joint inflammation and an imbalance between different T helper (Th) subsets. Vasoactive intestinal peptide (VIP) is a mediator that modulates all the stages comprised between the arrival of pathogens and Th cell differentiation in RA through its known anti-inflammatory and immunomodulatory actions. This “neuroimmunopeptide” modulates the pathogenic activity of diverse cell subpopulations involved in RA as lymphocytes, fibroblast-like synoviocytes (FLS), or macrophages. In addition, VIP decreases the expression of pattern recognition receptor (PRR) such as toll-like receptors (TLRs) in FLS from RA patients. These receptors act as sensors of pathogen-associated molecular pattern (PAMP) and damage-associated molecular pattern (DAMP) connecting the innate and adaptive immune system. Moreover, VIP modulates the imbalance between Th subsets in RA, decreasing pathogenic Th1 and Th17 subsets and favoring Th2 or Treg profile during the differentiation/polarization of naïve or memory Th cells. Finally, VIP regulates the plasticity between theses subsets. In this review, we provide an overview of VIP effects on the aforementioned features of RA pathology.

show abstract

“…34 Activation of immune inflammatory responses in RA cause synovial vascular inflammation and joint swelling, which is caused by leukocyte migration from the vasculature and infiltration into the synovium. 17,35 The cellular composition of synovitis in RA includes both innate and adaptive immune cells such as monocyte-lineage cells, dendritic cells, mast cells, osteoclasts, type 1 and 17 T-helper cells, Bcells and plasma cells. 17,21 A robust tissue response by synovial fibroblasts together with enhanced chondrocyte catabolism and synovial osteoclastogenesis promotes articular destruction.…”

mentioning

confidence: 99%

The genetic pathogenesis, diagnosis and therapeutic insight of rheumatoid arthritis

Zamanpoor

2019

Clinical Genetics

View full text Add to dashboard Cite

Rheumatoid arthritis (RA) is a systemic autoimmune disease that causes chronic inflammation of the joints. RA is a heterogeneous disorder caused by an abnormal autoimmune response triggered by the complex interactions of genetic and environmental factors that contribute to RA etiology. However, its underlying pathogenic mechanisms are yet to be fully understood. In this review, I provide an overview of the pathogenesis, diagnosis and therapeutic insight in the clinical management of RA in light of the recent updates to classification criteria and recent discoveries of genetic loci associated with susceptibility for RA.

show abstract

Driving chronicity in rheumatoid arthritis: perpetuating role of myeloid cells

Cited by 36 publications

References 115 publications

TNF-induced inflammatory genes escape repression in fibroblast-like synoviocytes: transcriptomic and epigenomic analysis

TNF-induced inflammatory genes escape repression in fibroblast-like synoviocytes: transcriptomic and epigenomic analysis

The Anti-Inflammatory Mediator, Vasoactive Intestinal Peptide, Modulates the Differentiation and Function of Th Subsets in Rheumatoid Arthritis

The genetic pathogenesis, diagnosis and therapeutic insight of rheumatoid arthritis

Contact Info

Product

Resources

About