Involvement of caspase‐1 in inflammasomes activation and bacterial clearance in S. aureus ‐infected osteoblast‐like MG ‐63 cells

Abstract

Staphylococcus aureus, a versatile Gram-positive bacterium, is the main cause of bone and joint infections (BJI), which are prone to recurrence. The inflammasome is an immune signaling platform that assembles after pathogen recognition. It activates proteases, most notably caspase-1 that proteolytically matures and promotes the secretion of mature IL-1β and IL-18. The role of inflammasomes and caspase-1 in the secretion of mature IL-1β and in the defence of S. aureus-infected osteoblasts has not yet been fully investigated. We show here that S. aureus-infected osteoblast-like MG-63 but not caspase-1 knockout CASP1-/-MG-63 cells, which were generated using CRISPR-Cas9 technology, activate the inflammasome as monitored by the release of mature IL-1β. The effect was strain-dependent. The use of S. aureus deletion and complemented phenole soluble modulins (PSMs) mutants demonstrated a key role of PSMs in inflammasomes-related IL-1β production. Furthermore, we found that the lack of caspase-1 in CASP1-/-MG-63 cells impairs their defense functions, as bacterial clearance was drastically decreased in CASP1-/-MG-63 compared to wild-type cells. Our results demonstrate that osteoblast-like MG-63 cells play an important role in the immune response against S. aureus infection through inflammasomes activation and establish a crucial role of caspase-1 in bacterial clearance.

Staphylococcus aureus Internalization in Osteoblast Cells: Mechanisms, Interactions and Biochemical Processes. What Did We Learn from Experimental Models?

“…This evidence suggest that the lack of caspase-1 impairs the ability of osteoblast-like cells to limit S. aureus growth. A drastic increase in the proliferation of internalized bacteria in osteoblastic mutant cells has already been highlighted [62] (Figure 5). In fact, a correlation exists between the lack of caspase-1 activation and a failure in limiting S. aureus replication inside phagocytic cells [99,100].…”

“…This binding leads to the autocatalytic cleavage of caspase-1, the processing of pro-IL-1β and pro-IL-18 and the secretion of mature IL-1β and IL-18, triggering in some cases even an inflammatory form of cell death (pyroptosis) [61]). Recent studies have shown that this also applies to S. aureus and MG-63 cells [62,63].…”

“…Six hours after the beginning of the infection with a 50:1 MOI, the number of S. aureus CFUs recovered from mutant cells was significantly higher than those recovered from WT MG-63 cells. WT MG-63 cells and CASP1−/− mutant MG-63 clones expressed apoptosis-associated speck-like protein, while only WT MG-63 produced IL-1β after exposure to inflammasome [62].…”

Consequences of Metabolic Interactions during Staphylococcus aureus Infection

“…These toxins, particularly Hla, activate a brisk host response, consisting of IL-1β production [ 22 ]. It has long been appreciated that IL-1β is a critical host factor in the pathogenesis of cutaneous S. aureus infection [ 29 ] and has a major role in S. aureus killing and clearance [ 29 , 30 ]. Mice deficient in IL-1β ( Il1- β −/− ) developed larger lesions with higher bacterial burdens and reduced neutrophil recruitment following subcutaneous injection compared to parental strain mice [ 29 ].…”

Poor Implant Retention Rate in Patients Treated with Beta-Lactam Antibiotics for Initial Intravenous Empirical Therapy in Acute Periprosthetic Knee Joint Infection

“…Acute PJI becomes di cult to eradicate in the chronic phase as the causative organisms can form mature bio lms and some organisms may parasitize osteoblasts [7,8]. Thus, eradication of the causative organisms in the acute phase with optimal initial intravenous empirical therapy would increase implant retention rate because the absolute number of causative organisms is at a minimum when the irrigation and debridement surgery is performed.…”