The Role of NLPR3 Inflammasome in Response to Thermal Injury and Sepsis

Although the induction of acute-phase inflammation after burn injury is essential, if prolonged it can induce increased risk of infection and sepsis. The NLRP3 inflammasome has established itself as an integral mediator of the acute phase response, however there is a current lack of understanding how it is involved in the inflammatory response after burn injury. In this study we investigated the role of the NLRP3 inflammasome in burn and septic patients and further aimed to determine if its components can be used to predict sepsis. In Chapter 2 we established the hyperinflammatory response in adult burn and septic burn patients. We also showed that there is increased NLRP3 inflammasome activation and expression in white adipose tissue (WAT) of burn patients and that its pro-inflammatory by-products increase with increasing injury severity. In Chapter 3, we studied the effect that NLRP3 knockout would have on survival and the immune response in rodents. Interestingly, knocking out NLRP3 inflammasome resulted in increased bacterial clearance and survival in rodents. However, it also induced greater acute responsiveness at the site of injury and WAT characterized by greater macrophage and neutrophil infiltration, ER stress, apoptosis/pyroptosis, and increased systemic inflammation. Differential effects were found in other organs with an overall faster return to baseline in inflammatory mediators. In septic burn patients, we found peaks in WAT NLRP3 gene expression occurring later than non-septic’s. Extending these findings in Chapter 4, we used the major source of NLRP3 inflammasome (macrophages) and its by-product (IL-1β) to generate the Septic Predictor Index to identify burn patients susceptible to sepsis. Patients with Index ratios greater than 0.5 had reduced macrophages proportions in WAT that were producing excess amounts of pro-inflammatory IL- 1β, and subsequently developed sepsis. Collectively, these results suggest that the NLRP3 inflammasome is a critical acute-phase mediator in septic burn patients and despite its utility to identify patient susceptible to sepsis, its mechanism is complex yet protective of sepsis development.Ph.D