NLRP3 Knockout Enhances Immune Infiltration and Inflammatory Responses and Improves Survival in a Burn-Sepsis Model.

Although sepsis in burn patients is a major contributor to mortality, treatments are not always effective and underlying mechanisms have yet to be completely elucidated. NLRP3 inflammasome orchestrates burn-induced, inflammatory-driven pathophysiologic processes. Here, we determined the mechanism of NLRP3 inflammasome activation on bacterial clearance and mortality in burn-sepsis. We obtained tissue and blood from 30 wild-type and 30 Nlrp3-/- mice. Mice were subjected to a two-hit model of 25-30% TBSA scald burn followed by Pseudomonas aeruginosa wound infection 72 hours after injury. We also obtained tissue from 34 adult burn patients (≥ 18 years of age) with early (0-11 days post-burn) and later (≥12 days post-burn) surgical time points and ten healthy controls. Murine studies indicated that Nlrp3-/- had 30% improved survival and bacterial clearance at the site of injury and systemically relative to burn-sepsis wild-type. Greater macrophage and neutrophil infiltration occurred acutely after infection (12-hours) to the site of injury and adipose tissue. This was followed by increased macrophage and neutrophil infiltration to lymphoid organs and liver beyond the acute phase (24- and 72-hours). Interestingly, Nlrp3 ablation increased acute systemic inflammation (IL-6, TNF-α, IL-1β). Septic burn patients had persistently increased adipose NLRP3 byproduct expression beyond the acute phase that was more pronounced in late-onset sepsis. Our findings suggest that Nlrp3 genetic ablation enhanced acute tissue-specific inflammatory responsiveness. Likely, this occurs by paradoxically increasing acute immune infiltration and inflammation with a non-persistent response. Clinically, persistent NLRP3-mediated inflammation occurs in septic versus normal burn patients and potentially detrimentally impacts patient outcomes.