Blocking TNF-α enhances Pseudomonas aeruginosa-induced mortality in burn mice through induction of IL-1β

• Pseudomonas aeruginosa infection with burn enhanced lung damage and mortality in Tnfrsf1a−/− mice.
• P. aeruginosa injection with burn induced IL-1β expression in the lung in Tnfrsf1a−/− mice.
• IL-1 receptor antagonist reduced P. aeruginosa with burn-induced mortality in Tnfrsf1a−/− mice.
• IL-1 receptor antagonist decreased P. aeruginosa with burn-induced IL-1β in lung.
• Burn induced NF-κB activation and neutrophil in lung were alleviated in Tnfrsf1a−/− mice.

PurposeTumor necrosis factor (TNFα) is a proinflammatory cytokine and has been a target for intervention in human sepsis. However, inhibition of TNF-α with a high dose of a TNF-receptor fusion protein in patients with septic shock worsened patient survival. This study was designed to investigate whether blocking TNF-α enhances mortality in infected burn mice through the induction of IL-1β.MethodsWT or Tnfrsf1a−/− mice received Pseudomonas aeruginosa injection in the back at 8 h after burn injury. The animals were sacrificed at 24 h after burn and lung tissues were harvested and examined for determining myeloperoxidase (MPO) activity, pulmonary microvascular dysfunction, NF-κB DNA binding activity, and IL-1β expression. Also, the lung and blood were harvested for bacterial count assay.ResultThermal injury alone induced NF-κB DNA binding activity and neutrophil infiltration in the lung in WT but not in Tnfrsf1a−/− mice. A 50% total body surface area (TBSA) burn induced a significant increase of mortality in WT compared with Tnfrsf1a−/− mice. In contrast, P. aeruginosa injection with a 30% TBSA burn pretreatment enhanced IL-1β expression, bacterial counts in lung and blood, pulmonary microvascular dysfunction, and mortality in Tnfrsf1a−/− mice compared with WT mice. Injection of the IL-1 receptor antagonist, Anakinra, reduced P. aeruginosa infection with burn pretreatment-induced blood bacterial counts, IL-1β levels as well as permeability of lung, and mortality in Tnfrsf1a−/− mice.ConclusionsOur findings suggest that thermal injury induces lung NF-κB activation and neutrophil sequestration through TNFα signaling. However, blocking TNF-α enhances P. aeruginosa infection-induced lung damage in burn mice via induction of IL-1β. Using an IL-1 receptor antagonist combined with the neutralization of TNF-α could be a useful strategy for decreasing P. aeruginosa infection-induced mortality in burn patients.