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Suppression of inflammatory arthritis by the parasitic worm product ES-62 is associated with epigenetic changes in synovial fibroblasts
- Source :
- PLoS Pathogens, PLoS Pathogens, Vol 17, Iss 11, p e1010069 (2021), PLoS Pathogens, Vol 17, Iss 11 (2021)
- Publication Year :
- 2021
-
Abstract
- ES-62 is the major secreted protein of the parasitic filarial nematode, Acanthocheilonema viteae. The molecule exists as a large tetramer (MW, ~240kD), which possesses immunomodulatory properties by virtue of multiple phosphorylcholine (PC) moieties attached to N-type glycans. By suppressing inflammatory immune responses, ES-62 can prevent disease development in certain mouse models of allergic and autoimmune conditions, including joint pathology in collagen-induced arthritis (CIA), a model of rheumatoid arthritis (RA). Such protection is associated with functional suppression of “pathogenic” hyper-responsive synovial fibroblasts (SFs), which exhibit an aggressive inflammatory and bone-damaging phenotype induced by their epigenetic rewiring in response to the inflammatory microenvironment of the arthritic joint. Critically, exposure to ES-62 in vivo induces a stably-imprinted CIA-SF phenotype that exhibits functional responses more typical of healthy, Naïve-SFs. Consistent with this, ES-62 “rewiring” of SFs away from the hyper-responsive phenotype is associated with suppression of ERK activation, STAT3 activation and miR-155 upregulation, signals widely associated with SF pathogenesis. Surprisingly however, DNA methylome analysis of Naïve-, CIA- and ES-62-CIA-SF cohorts reveals that rather than simply preventing pathogenic rewiring of SFs, ES-62 induces further changes in DNA methylation under the inflammatory conditions pertaining in the inflamed joint, including targeting genes associated with ciliogenesis, to programme a novel “resolving” CIA-SF phenotype. In addition to introducing a previously unsuspected aspect of ES-62’s mechanism of action, such unique behaviour signposts the potential for developing DNA methylation signatures predictive of pathogenesis and its resolution and hence, candidate mechanisms by which novel therapeutic interventions could prevent SFs from perpetuating joint inflammation and destruction in RA. Pertinent to these translational aspects of ES-62-behavior, small molecule analogues (SMAs) based on ES-62’s active PC-moieties mimic the rewiring of SFs as well as the protection against joint disease in CIA afforded by the parasitic worm product.<br />Author summary The Hygiene Hypothesis proposes that the recent eradication of parasitic worms and other pathogens has resulted in chronically unbalanced, hyperactive immune systems that likely contribute to the corresponding dramatically increased incidence of allergic, autoimmune and metabolic conditions worldwide. Collectively, epidemiological and experimental animal model data supporting this hypothesis have focused interest in developing “helminth therapies”, based on infections with worms or their immunomodulatory products. Reflecting this, ES-62, an anti-inflammatory protein we discovered in the secretions of the filarial nematode Acanthocheilonema viteae, can prevent disease initiation and progression in mouse models of asthma, dermatitis, RA, SLE and the comorbidities arising from obesity-accelerated ageing. We now show that its protection against arthritis is associated with an ability to stably reprogram stromal cells in the joint away from a pathogenic bone-damaging population to a novel “safe” phenotype. Signposting of such pathogenic and “safe” molecular signatures may now provide starting points for developing novel therapies to prevent joint disease in RA. In the broader context, our discovery that a defined parasitic worm product can reprogram host cell responses furthers both our understanding of the host-pathogen interaction and identifies new directions for developing anthelmintics and therapies to resolve inflammation and induce tissue repair in humans.
- Subjects :
- Male
Cell signaling
Physiology
Inflammatory arthritis
Anti-Inflammatory Agents
Arthritis
Signal transduction
ERK signaling cascade
Biochemistry
Epigenesis, Genetic
Mice
0302 clinical medicine
Skeletal Joints
Immune Physiology
Medicine and Health Sciences
Biology (General)
Musculoskeletal System
Immune Response
Cells, Cultured
0303 health sciences
Innate Immune System
DNA methylation
Chemical Reactions
Signaling cascades
Acanthocheilonema
Helminth Proteins
Phenotype
Synoviocytes
Chromatin
3. Good health
Cell biology
Nucleic acids
STAT signaling
Chemistry
Mice, Inbred DBA
QR180
Physical Sciences
Cytokines
Epigenetics
medicine.symptom
Anatomy
DNA modification
Chromatin modification
Research Article
Chromosome biology
musculoskeletal diseases
QH301-705.5
Immunology
Inflammation
Biology
Microbiology
Methylation
03 medical and health sciences
Signs and Symptoms
Downregulation and upregulation
Virology
medicine
Genetics
Animals
Molecular Biology
Skeleton
030304 developmental biology
Acanthocheilonema viteae
Biology and life sciences
DNA
RC581-607
Fibroblasts
Molecular Development
medicine.disease
biology.organism_classification
Arthritis, Experimental
Immune System
Parasitology
Gene expression
Immunologic diseases. Allergy
Clinical Medicine
030215 immunology
Developmental Biology
Subjects
Details
- ISSN :
- 15537374 and 15537366
- Volume :
- 17
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- PLoS pathogens
- Accession number :
- edsair.doi.dedup.....767e5006ec12c89eda9a2ee9e35f9a2d