# Treatment of CGD with the PPAR-gamma agonist, pioglitazone, enhances phagocyte anti-inflammatory and antimicrobial responses > **NIH NIH U01** · NATIONAL JEWISH HEALTH · 2020 · $168,825 ## Abstract Project Summary/Abstract: 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 PPARγ, 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 PPARγ 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 PPARγ and possibly by PPARγ-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) PPARγ 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 PPARγ 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 PPARγ and to mitochondrial oxidant production is likely to provide insights into other chronic inflammatory conditions and potentially a means of enhancing host defense in chron... ## Key facts - **NIH application ID:** 9879669 - **Project number:** 5U01AI122269-03 - **Recipient organization:** NATIONAL JEWISH HEALTH - **Principal Investigator:** DONNA L BRATTON - **Activity code:** U01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $168,825 - **Award type:** 5 - **Project period:** 2018-03-12 → 2020-08-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/9879669 ## Citation > US National Institutes of Health, RePORTER application 9879669, Treatment of CGD with the PPAR-gamma agonist, pioglitazone, enhances phagocyte anti-inflammatory and antimicrobial responses (5U01AI122269-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9879669. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*