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Robust COX-2-mediated prostaglandin response may drive arthralgia and bone destruction in patients with chronic inflammation post-chikungunya
- Source :
- PLoS Neglected Tropical Diseases, PLoS Neglected Tropical Diseases, 2021, 15 (2), pp.e0009115. ⟨10.1371/journal.pntd.0009115⟩, PLoS Neglected Tropical Diseases, Vol 15, Iss 2, p e0009115 (2021), PLoS Neglected Tropical Diseases, Public Library of Science, 2021, 15 (2), pp.e0009115. ⟨10.1371/journal.pntd.0009115⟩
- Publication Year :
- 2021
- Publisher :
- HAL CCSD, 2021.
-
Abstract
- Patients following infection by chikungunya virus (CHIKV) can suffer for months to years from arthralgia and arthritis. Interestingly, methotrexate (MTX) a major immune-regulatory drug has proved to be of clinical benefit. We have previously shown that CHIKV can persist in the joint of one patient 18 months post-infection and plausibly driving chronic joint inflammation but through ill-characterized mechanisms. We have pursued our investigations and report novel histological and in vitro data arguing for a plausible role of a COX-2-mediated inflammatory response post-CHIKV. In the joint, we found a robust COX-2 staining on endothelial cells, synovial fibroblasts and more prominently on multinucleated giant cells identified as CD11c+ osteoclasts known to be involved in bone destruction. The joint tissue was also strongly stained for CD3, CD8, CD45, CD14, CD68, CD31, CD34, MMP2, and VEGF (but not for NO synthase and two B cell markers). Dendritic cells were rarely detected. Primary human synovial fibroblasts were infected with CHIKV or stimulated either by the synthetic molecule polyriboinosinic:polyribocytidylic acid (PIC) to mimic chronic viral infection or cytokines. First, we found that PIC and CHIKV enhanced mRNA expression of COX-2. We further found that PIC but not CHIKV increased the mRNA levels of cPLA2α and of mPGES-1, two other central enzymes in PGE2 production. IFNβ upregulated cPLA2α and COX-2 transcription levels but failed to modulated mPGES-1 mRNA expression. Moreover, PIC, CHIKV and IFNβ decreased mRNA expression of the PGE2 degrading enzyme 15-PGDH. Interestingly, MTX failed to control the expression of all these enzymes. In sharp contrast, dexamethasone was able to control the capacity of pro-inflammatory cytokines, IL-1β as well as TNFα, to stimulate mRNA levels of cPLA2α, COX-2 and mPGES-1. These original data argue for a concerted action of CHIKV (including viral RNA) and cytokines plausibly released from recruited leukocytes to drive a major COX-2-mediated PGE2 proinflammatory responses to induce viral arthritis.<br />Author summary It is important to have a better understanding of the immuno-pathogenesis of Chikungunya virus (CHIKV) and particularly focusing on the chronic phase associated to arthralgia and arthritis. Benefiting from our prospective cohort studies, we herein provide novel in vivo data identifying for the first time the implication of COX-2 and several other enzymes involved in prostaglandin biosynthesis and the persistence of the virus on the joint. Prostaglandin has major activities in inflammation and joint destruction. In vitro, we have used a model of human synovial fibroblasts to decipher the regulatory mechanisms of prostaglandin biosynthesis pathway. We have made important observations showing that the virus itself as well as major inflammatory cytokines can dramatically control the expression of all enzymes involved in the metabolism of prostaglandin. Interestingly, pharmacological investigations further revealed that dexamethasone, but not methotrexate (currently used to treat patients with chikungunya) may be of clinical values.
- Subjects :
- 0301 basic medicine
RNA viruses
Viral Diseases
Prostaglandin
Physiology
[SDV]Life Sciences [q-bio]
RC955-962
Interleukin-1beta
Arthritis
Pathology and Laboratory Medicine
Biochemistry
0302 clinical medicine
Medical Conditions
Viral arthritis
Animal Cells
Arctic medicine. Tropical medicine
Immune Physiology
Medicine and Health Sciences
Lipid Hormones
Immune Response
Connective Tissue Cells
Innate Immune System
Chikungunya Virus
virus diseases
Arthralgia
3. Good health
[SDV] Life Sciences [q-bio]
medicine.anatomical_structure
Infectious Diseases
Medical Microbiology
Connective Tissue
Viral Pathogens
Viruses
Cytokines
Tumor necrosis factor alpha
medicine.symptom
Public aspects of medicine
RA1-1270
Pathogens
Cellular Types
Anatomy
Research Article
Neglected Tropical Diseases
CD14
Alphaviruses
Immunology
Inflammation
Microbiology
Dinoprostone
Proinflammatory cytokine
Togaviruses
03 medical and health sciences
Signs and Symptoms
Rheumatology
medicine
Humans
RNA, Messenger
Microbial Pathogens
B cell
030203 arthritis & rheumatology
Biology and life sciences
business.industry
Tumor Necrosis Factor-alpha
Public Health, Environmental and Occupational Health
Organisms
Endothelial Cells
Chikungunya Infection
Proteins
Cell Biology
Fibroblasts
Molecular Development
medicine.disease
Tropical Diseases
Hormones
030104 developmental biology
Methotrexate
Biological Tissue
Cyclooxygenase 2
Immune System
Prostaglandins
Chikungunya Fever
Interferons
Clinical Medicine
business
CD8
Developmental Biology
Subjects
Details
- Language :
- English
- ISSN :
- 19352727 and 19352735
- Database :
- OpenAIRE
- Journal :
- PLoS Neglected Tropical Diseases, PLoS Neglected Tropical Diseases, 2021, 15 (2), pp.e0009115. ⟨10.1371/journal.pntd.0009115⟩, PLoS Neglected Tropical Diseases, Vol 15, Iss 2, p e0009115 (2021), PLoS Neglected Tropical Diseases, Public Library of Science, 2021, 15 (2), pp.e0009115. ⟨10.1371/journal.pntd.0009115⟩
- Accession number :
- edsair.doi.dedup.....27088abcd496fe584741847392b3534a