Investigation of the role of toll-like and interleukin-6 receptors in peritoneal inflammatory responses to infection

Bacterial infection is a feature of long-term peritoneal dialysis (PD) and a cause of loss of peritoneal function and treatment failure. Understanding how local inflammation is initiated and peritoneal host defence mechanisms are activated in PD patients is key to reducing the detrimental consequences of peritonitis. The capacity of human peritoneal mesothelial cells (HPMC) to ingest bacteria has been described, and the ability of the Toll-like family of innate immune receptors (TLR) to trigger inflammatory responses to pathogens has been demonstrated. However, the pathogen recognition ability, the potential role of TLRs, the specific role in the early inflammatory response, and the regulation of HPMC’ putative ability for pathogen recognition have not been fully investigated. To address these issues, the present study aimed at characterising TLR expression and responses in HPMC and evaluating the capacity of modulators of pro-inflammatory responses, namely soluble TLR2 (sTLR2) and the IL-6/sIL-6R complex, to regulate TLR-mediated HPMC and peritoneal responses in vitro and in vivo. HPMC were found to respond to an array of bacterial pathogens via expression and function of a specific set of TLRs. HPMC responses were susceptible to modulation by sTLR2 and sIL-6R, resulting in inhibition of TLR2-driven HPMC responses. In vivo, sTLR2 and IL-6/sIL- 6R reduced neutrophil influx partly by inhibiting NF-κB activation in stromal cells of the peritoneum. IL-6 signalling counteracted TLR2-mediated responses by reducing peritoneal leukocyte recruitment and chemokine production. Notably, following the establishment of a mouse model of peritoneal bacterial infection, IL-6 signalling was confirmed to be beneficial to bacterial clearance. The results of this thesis confirm and extend the knowledge of the pivotal role that HPMC play in peritoneal responses to infection. The capacity of sTLR2 and IL-6/sIL-6R to modulate peritoneal responses demonstrated in this study may inform the design of new therapeutic strategies to reduce PD-associated peritonitis and thus improve treatment outcomes