Feature of NETosis in Chronic Granulomatous Disease and Its Impact on Renal Disorder

Chronic granulomatous disease (CGD) is an inherited immunodeficiency characterized by impaired phagocytic cells due to mutations in genes encoding the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme complex, leading to recurrent severe infections. In the innate immune system, NETosis, which is a program for the formation of neutrophil extracellular traps (NETs) has been highlighted. Over the past years, NETs have been recognized as being involved in the pathogenesis of immune-mediated inflammatory renal diseases. On the mechanism underlying usual NETosis, reactive oxygen species (ROS) activation by NADPH oxidase (NOX) has been considered to be essential. CGD patients are theoretically unable to form such usual NETosis because of a deficiency of NOX-dependent ROS activation. However, according to previous reports, stimulated neutrophils derived from CGD patients showed NOX-independent unusual NETosis enriched in mitochondrial DNA. The mitochondrial ROS activation on NETosis in CGD was reported to induce an elevated inflammatory response, instead of the usual ROS generation, which might cause autoimmune diseases. We are interested in the renal autoimmune disorder in CGD, especially the inflamed renal disorder caused by unusual mitochondria-rich NETosis in CGD. Indeed, in vivo analysis has revealed severe renal disorder in MRL/lpr lupus-prone mice lacking NOX activity compared to wild-type of MRL/lpr. A few clinical reports showed aggravation of inflamed glomerulonephritis in patients with CGD. Taken together, we presumed that a defect of usual NOX-dependent NETosis might be a clue for aggravated renal disorder in CGD. In the present review, we summarize the features of NETosis in CGD and discuss the aggravation mechanism for renal disorder in CGD by referring to previous reports.