Chronic Granulomatous Disease (CGD) is a genetic disease resulting from mutations of the phagocyte NADPH oxidase. While loss of the functioning oxidase results in immunodeficiency, significant disease morbidity is associated with exaggerated, and often sterile inflammation (e.g. obstructing granuloma, colitis and autoimmunity). Specifically, it is hypothesized that absence of reactive oxygen species (ROS) from the NADPH oxidase results in: i) deficient display of signals on activated and dying CGD neutrophils needed to facilitate their recognition and clearance (efferocytosis) by macrophages, ii) deficient macrophage PPAR?, a master controller of programming for efferocytosis and anti-inflammatory functions, and iii) deficient crosstalk to phagocyte mitochondria for the production of additional oxidants needed for optimal microbial killing. It is hypothesized that pioglitazone, a PPAR? agonist approved for use in type 2 diabetes mellitus, will provide key signals bypassing the mutated NADPH oxidase in phagocytes. Specifically, it is hypothesized that pioglitazone will exert these effects both by its activation of PPAR? and possibly by PPAR?-independent alteration of mitochondria bioenergetics. To this end, pioglitazone treatment of CGD mice restored CGD macrophage/monocyte efferocytic capability and anti-inflammatory functions and also enhanced signaling by neutrophils for engulfment by macrophages. Importantly, after pioglitazone treatment, CGD phagocytes also showed enhanced mitochondrial oxidant production and partially restored bacterial killing. Preliminary data showed ex vivo pioglitazone treatment of human CGD monocytes had similar effects, and enhanced phagocyte responses have been demonstrated following the treatment of 3 CGD patients with pioglitazone. Translation of these preclinical and preliminary observations into a short-term clinical trial of pioglitazone in human CGD is proposed.
The specific aims of this trial will be to determine whether pioglitazone treatment of CGD patients will restore i) PPAR? signaling, efferocytosis and anti-inflammatory signaling in blood monocytes, ii) phagocyte mitochondrial ROS production for enhanced ROS-dependent killing of microbes, iii) signaling by CGD neutrophils for their enhanced clearance, and determine whether treatment will iv) reduce systemic markers of inflammation, Th17 lymphocytes, and colitic inflammation. In summary, a new hypothesis ties the functioning NADPH oxidase to PPAR? activation, phagocyte programming, and mitochondrial ROS production, and gives impetus to a novel approach using an ?on the shelf? therapeutic, pioglitazone, to ameliorate both exaggerated inflammation and immunodeficiency in CGD. Further, an improved understanding of signaling downstream of the NADPH oxidase to PPAR? and to mitochondrial oxidant production is likely to provide insights into other chronic inflammatory conditions and potentially a means of enhancing host defense in chronic/resistant bacterial infections.
Relevance to Public Health Mutations of the leukocyte NADPH oxidase underlie Chronic Granulomatous Disease (CGD), and patients with this disorder suffer from the inability to fight off infections with certain bacteria and fungi, and also suffer exaggerated inflammation, e.g. poor wound healing, obstructing granulomas, colitis, and autoimmunity. The lack of leukocyte oxidants from the defective NADPH oxidase leads to deficient signaling by a protein called PPAR?, a master regulator of anti-inflammatory controls on leukocytes, but also deficient production of oxidants from leukocyte mitochondria, cellular ?powerhouses,? that contribute to antimicrobial defenses. Pre- clinical (animal) trials of the PPAR? agonist pioglitazone, approved for use in type 2 diabetes mellitus, show promise for enhancing both PPAR? signaling and mitochondrial oxidant production downstream of the NADPH oxidase to restore these important leukocyte functions, and are the impetus for this proposed clinical trial of pioglitazone in patients with CGD.
