Inflammatory Joint Disease Is a Risk Factor for Streptococcal Sepsis and Septic Arthritis in Mice

Abstract

Septic arthritis is a medical emergency associated with high morbidity and mortality, yet hardly any novel advances exist for its clinical management. Despite septic arthritis being a global health burden, experimental data uncovering its etiopathogenesis remain scarce. In particular, any interplay between septic arthritis and preceding joint diseases are unknown as is the contribution of the synovial membrane to the onset of inflammation. Using C57BL/6 mice as a model to study sepsis, we discovered that Group A Streptococcus (GAS) – an important pathogen causing septic arthritis - was able to invade the articular microenvironment. Bacterial invasion resulted in the infiltration of immune cells and detrimental inflammation. In vitro infected fibroblast-like synoviocytes induced the expression of chemokines ( Ccl2 , Cxcl2 ), inflammatory cytokines ( Tnf , Il6 ), and integrin ligands (ICAM-1, VCAM-1). Apart from orchestrating immune cell attraction and retention, synoviocytes also upregulated mediators impacting on bone remodeling ( Rankl ) and cartilage integrity ( Mmp13 ). Using collagen-induced arthritis in DBA/1 × B10.Q F1 mice, we could show that an inflammatory joint disease exacerbated subsequent septic arthritis which was associated with an excessive release of cytokines and eicosanoids. Importantly, the severity of joint inflammation controlled the extent of bone erosions during septic arthritis. In order to ameliorate septic arthritis, our results suggest that targeting synoviocytes might be a promising approach when treating patients with inflammatory joint disease for sepsis.

Degenerative Joint Damage Is Not a Risk Factor for Streptococcal Sepsis and Septic Arthritis in Mice

“…Culture of GAS was performed as previously reported [ 6 ]. In short, bacteria were cultured in Todd Hewitt broth (Becton Dickinson) until mid-log phase.…”

“…Mice from all groups were administered tramadol to reduce pain immediately before infection and were monitored for a maximum of 14 days post-infection. A sepsis scoring system was used to detect humane endpoints, as previously described in an unblinded manner [ 6 ]. Activity of (septic) arthritis was scored according to a scheme that was previously described [ 6 , 10 ]: 1–5 points for swollen digits, 5 points for swollen metacarpus or metatarsus, 5 points for swollen ankle or wrist joints and 5 points if GAS was isolated from tibiofemoral joint swabs postmortem.…”

“…A sepsis scoring system was used to detect humane endpoints, as previously described in an unblinded manner [ 6 ]. Activity of (septic) arthritis was scored according to a scheme that was previously described [ 6 , 10 ]: 1–5 points for swollen digits, 5 points for swollen metacarpus or metatarsus, 5 points for swollen ankle or wrist joints and 5 points if GAS was isolated from tibiofemoral joint swabs postmortem. Mice were sacrificed by cervical dislocation, and blood, liver and spleen were collected.…”

“…Plasma cytokines were quantified using the LEGENDplex TM Mouse Inflammation Panel (BioLegend) according to the manufacturer’s instructions. GAS-specific antibodies were detected using an in-house enzyme-linked immunosorbent assay, as previously described [ 6 ]. Liver and spleen were homogenized and plated on agar for determination of bacterial burdens.…”

“…Epidemiological data suggest that patients with pre-existing joint disorders such as rheumatoid arthritis (RA) or osteoarthritis (OA) are at a high risk of developing SA [ 4 , 5 ]. We recently demonstrated that collagen-induced arthritis—a mouse model for RA—promoted the onset and severity of SA, which, in turn, was associated with immune dysregulation and increased mortality [ 6 ]. Using mouse models for human OA, we aimed to investigate if degenerative joint damage, by itself, also increases the risk for SA.…”