Dual neutralization of TNFR-2 and MMP-2 regulates the severity of S. aureus induced septic arthritis correlating alteration in the level of interferon gamma and interleukin-10 in terms of TNFR2 blocking

Abstract

Severity of S. aureus septic arthritis is correlated to prolonged inflammation by inflammatory cytokines like TNF-α, IL-1β, and IL-6 even after successful elimination of bacteria. Role of TNF-α via TNFR2 is not well established in this aspect. IFN-γ induces TNF-α release from the macrophages augmenting the inflammatory arthritis. IL-10 modulates the levels of pro-inflammatory cytokines promoting resolution of inflammation. TNF-α-TNFR2 signaling upregulates both of these cytokines. Higher level of MMP-2 induction by inflammatory cytokines during arthritis promotes tissue destruction. Whether dual neutralization of TNFR-2 and MMP-2 regulates the severity of S. aureus arthritis by modulating local and systemic cytokine milieu mainly due to TNFR-2 blocking was an obvious question. Here, we attempted the effects of neutralization of MMP-2 and TNFR2 on S. aureus arthritis and its impact on pro-inflammatory cytokines and some other parameters related to tissue destruction. Reduction in arthritis index was noticed in infected mice treated with both MMP-2 inhibitor and TNFR2 antibody. Lowest levels of inflammatory cytokines, iNOS, RANKL, NF-κb, JNK kinase, ROS, and MPO, and lysozyme activity were observed in combined neutralization group at 9 and 15 dpi, but at 3 dpi, most of the above parameters remained elevated due to TNFR2 neutralization. Diminished IL-10 and IFN-γ levels as a result of TNFR2 neutralization at early and later phase of infection respectively might be responsible for these contrasting effects. Overall, it can be suggested that administration of MMP-2 inhibitor and TNFR2 antibody in combination is protective against the inflammation and tissue destruction associated with S. aureus infection during the arthritic episode.

Expression and significance of autophagy genes LC3, Beclin1 and MMP-2 in endometriosis

“…Its enzymatic substrates are mainly type IV, V, VII, IX and X collagen, fibronectin and elastin. Therefore, MMP-2 plays a certain role in the process of tumor cell shedding, invasion and migration (25). According to the data displayed, the high expression of MMP-2 can enable it to exert strong proteolysis, degrade the basement membrane components around ectopic endometrial tissues, and affect the correlation among mesenchymal cells, thus invading the peritoneum.…”

Novel therapeutic interventions towards improved management of septic arthritis

“…Bacterial products and their toxins, cytokines such as TNF-α,IL-1β and also the transcription factor, NF-kB have been implicated inactivation of these endopeptidases. As a result, inflammatory cells, synovial fibroblasts, chondrocytes, resident articular cells, synovial fibroblasts, osteoclasts start the release of MMP’s thus adding to their heightened level s[ 167 , 172 – 174 ]. These elevated levels of MMP’s cause progressive bone and cartilage destruction in septic arthritis even after bacterial clearanc e[ 166 , 175 ].…”

“…These findings clearly indicate that neutralisation of MMP-2 represents a potential target to prevent joint destruction and regulate the cytokine levels during the arthritic episode. Further, Sultana and co-researchers [ 174 ] also evaluated the effect of combined therapy of MMP-2 and tumor necrosis factor receptor 1 antibody (TNFR1) on episodes of S. aureus induced septic arthritis in mice. Combined treatment group showed marked reduction in bacterial counts and low levels of pro-inflammatory cytokines in serum and synovial tissues as well as low arthritis index.…”

Exploring the Role of Staphylococcus aureus in Inflammatory Diseases

“…In septic arthritis caused by S. aureus infection, S. aureus activates immune cell-specific macrophages and DCs to release pro-inflammatory mediators, such as TNF-α, IL-1β, IL-6, and IL-21, which induce RORγt, RORγt, and CD4 T cells to differentiate into Th17 cells [ 182 , 183 , 184 ]. Th17 cells produce the pro-inflammatory cytokine IL-17, which directly stimulates arthritic inflammation by binding to receptors on immune cells, stimulating the production of more pro-inflammatory cytokines, chemokines, and other inflammatory mediators, including NO and MMPs, while TNF-α, IL-1β, and IL-6 upregulate MMPs, which can promote cartilage degradation and enhance joint destruction [ 185 , 186 ].…”