Pioglitazone restores mitochondrial oxidant production in CGD phagocytes and enhances their bactericidal capacity

In addition to having a nonfunctional NADPH oxidase, activated phagocytes from patients with chronic granulomatous disease (CGD) and gp91phox-/- mice (modeling X-linked CGD) lack oxidant production from mitochondria, as reported by authors Fernandez-Boyanapalli et al (http://www.jacionline.org/article/S0091-6749%2814%2901576-0/abstract) . Specifically, neutrophils and monocytes from blood, as well as recruited neutrophils and macrophages from inflamed tissues of CGD mice, failed to produce mitochondrial oxidants when activated. Deficient mitochondrial oxidant production was shown to contribute to impaired bactericidal activity against Staphylococcus aureus and Burkholderia cepacia in vitro. Importantly, the researchers demonstrated that mitochondrial oxidant production was restored (see Figure) following short-term treatment of CGD mice with pioglitazone, a PPAR? agonist approved for treatment of type 2 diabetes. Pioglitazone is known to induce metabolic changes that mimic “starvation signaling,” including altering mitochondrial functions. Treatment of CGD mice with pioglitazone restored the bactericidal activity of their phagocytes to approximately 30% of normal murine phagocytes and enhanced early bacterial clearance of S aureus in a peritonitis model. Treatment of monocytes from X-linked CGD patients with pioglitazone ex vivo similarly restored mitochondrial oxidant production supporting the hypothesis that pioglitazone may be useful therapeutically in the treatment of CGD.