Robust COX-2-mediated prostaglandin response may drive arthralgia and bone destruction in patients with chronic inflammation post-chikungunya

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.

MBZM-N-IBT, a Novel Small Molecule, Restricts Chikungunya Virus Infection by Targeting nsP2 Protease Activity In Vitro , In Vivo , and Ex Vivo

“…3A and H ). Because COX-2 is a key enzyme that is overexpressed during inflammation ( 27 ), its level was estimated following infection and treatment; although its level was higher by 10-fold, the same was downregulated by MBZM-N-IBT (3-fold) ( Fig. 3A and I ).…”

Decrypting the cellular and molecular intricacies associated with COVID-19-induced chronic pain

“… Myalgia 17.8% Before the emergence of respiratory tract symptoms Persistent, widespread Elevated CRP, ferritin, and LDH levels Elevated creatine kinase (CK) level Fibromyalgia, Myositis (Murat et al 2021 ) 4. Arthralgia 17.8% Variable onset mostly during or after COVID-19 infection Proximal muscle weakness, joint pain, Guillain-Barré syndrome (GBS) may appear as post-viral consequence Elevated CK level, IL-6 ferritin and d-dimer Cytokinetic storm, PG and COX-2 mediated inflammatory mechanisms (Ono et al 2020 ; Shah et al 2020 ; Bedoui et al 2021 ) 5. Abdominal pain 30% Early phase of COVID-19 Abdominal tenderness, sharp pain in periumbilical region Lymphopenia, Elevated d-dimer and CRP Cytokinetic storm, thromboembolism (Kim et al 2020 ; Mahan et al 2020 ) 6.…”

“…The arachidonic pathway is one of the common pathways responsible for inducing pain in patients as a result of injury, inflammation or infection. Prostaglandins, specifically are found to be involved in the initiation of pain as an anti-viral immune response in different viral diseases such as chikungunya and influenza (Full and Gack 2014 ; Sander et al 2017 ; Bedoui et al 2021 ). Prostaglandins (PGs) are physiologically active lipid compounds that are synthesized at the site of injury and are crucial mediators of central and peripheral sensitization.…”

“…The prostaglandin pathway can also explain the occurrence of testicular pain in COVID-19 (Kim et al 2020 ) patients as the lipids present in human testes consist of polyunsaturated fatty acids including arachidonic acid and COX-2 is abundantly expressed in the Leydig cells of human testes. Post-viral arthralgia is another consequence of COVID-19 which can be found to be mediated by PG and COX-2 mediated inflammatory mechanisms (Ono et al 2020 ; Bedoui et al 2021 ). Increased activity of COX-2 along with upregulated PGE2 production in found prominent in the joint tissues.…”

“…Increased activity of COX-2 along with upregulated PGE2 production in found prominent in the joint tissues. In many studies, prostaglandins have been actively associated with pain development in post-viral arthralgia conditions as a result of CHIKV infection (Bedoui et al 2021 ). Similarly, joint pain and inflammation have been observed in COVID-19 patients in the later phase of the disease (Mourão 2020 ).…”