Neutrophil-derived TNF drives fungal acute lung injury in chronic granulomatous disease.

Chronic granulomatous disease (CGD) results from NADPH oxidase deficiency and impaired reactive oxygen species (ROS) generation. This results in impaired killing of Aspergillus and, independently, a pathologic hyperinflammatory response to the organism. We hypothesized that neutrophil-derived ROS inhibit the inflammatory response to Aspergillus, and acute lung injury in CGD is due to failure of this regulation. Mice with gp91phox-deficiency, the most common CGD mutation, had more severe lung injury, neutrophil infiltration, and lung TNF after Aspergillus challenge compared to wildtypes. Neutrophils were surprisingly the predominant source of TNF in gp91phox-deficient lungs. TNF neutralization inhibited neutrophil recruitment in gp91phox-deficient mice and protected from lung injury. We propose that, in normal hosts, Aspergillus stimulates TNF-dependent neutrophil recruitment to the lungs and neutrophil-derived ROS limit inflammation. In CGD, in contrast, recruited neutrophils are the dominant source of TNF, promoting further neutrophil recruitment in a pathologic positive-feedback cycle, resulting in progressive lung injury.