A imunidade treinada promove modificações em macrófagos sinoviais e agrava o processo inflamatório da artrite infecciosa causada por Staphylococcus aureus

Abstract

The concept of trained immunity is based on an enhanced, non-specific response against a stimulus after primary exposure to certain microbial and non-microbial components, which results in epigenetic and metabolic reprogramming in the trained cell. The trained immunity mechanisms have been elucidated on classical innate immune cells, but the study of this event in resident synovial cells and how it could be responsible for the increase in joint inflammation is still scarce. We used a dual stimulation model, with LPS as the primary inflammatory stimulus and the induction of inflammatory arthritis by S. aureus as the secondary stimulus, and analyzed whether and which synoviocytes would develop a trained immunity phenotype that could result in increased joint inflammation after secondary joint infection. Our results show that double stimulation (LPS – S. aureus) increases inflammation markers in synoviocyte populations and promotes tissue damage and increased nociceptive response when compared to mice receiving a single injection of S. aureus. However, increased inflammation did not result in S. aureus clearance. LPS - S. aureus group increased the population of synovial macrophages, including a more specific population of CX3CR1+, showed an increased component of the mTOR pathway (p-mTOR and HIF1α) and the epigenetic marker H3K4me3. Treatment with mTOR inhibitor promoted a reduction in trained immunity phenotype, with a reduction in joint inflammation and bone damage. In conclusion, the trained immunity phenotype presented in CX3CR1+ synovial macrophages suggest a possibility to explain what happens to synovial cells during S. aureus infection, which seems to be responsible for inflammation and increased tissue damage by S. aureus.