579
Impaired Efferocytosis and Production of Mitochondrial Reactive Oxygen Species (mitoROS) By Monocytes in Human Chronic Granulomatous Disease (CGD) Is Reversed By Treatment with the Ppargamma Agonist Pioglitazone (Pio)
Sunday, March 6, 2016: 1:30 PM
Room 403B (Convention Center)
Donna Bratton, MD, , , , ,
Rationale: Efferocytosis, the clearance of dying cells, by murine CGD monocytes (Mo) and macrophages (Mφ) is impaired and associated with exaggerated inflammation. Pio treatment of CGD mice alters Mo/MΦ metabolism (increases mitoROS) and normalizes efferocytic capability, and enhances resolution of inflammation. We hypothesized that human CGD Mo (vs. normal Mo) would also have impaired efferocytosis and production of mitoROS reversible by Pio treatment in vitro and in vivo

Methods: Human CGD and normal Mo were tested for efferocytic capability and stimulated mitoROS production with and without Pio treatment. 

Results: CGD Mo of several genotypes were tested for efferocytic capability either fresh or following brief culture. In comparison to normal Mo, CGD Mo were significantly impaired in their efferocytosis of apoptotic Jurkat cells or carboxylated beads (apoptotic cell mimics). Overnight culture of CGD Mo with Pio reversed the impairment. MitoROS was assessed in stimulated Mo and found to be significantly diminished in CGD Mo, but was restored following culture with Pio. Mo were then isolated from two CGD patients before and during Pio treatment for inflammatory bowel disease (IBD). CGD/IBD Mo showed impaired efferocytosis compared to normal Mo at baseline. Pio treatment of the CGD/IBD patients resulted in enhanced efferocytic capability over time of Pio treatment. MitoROS production was similarly restored in Mo from CGD/IBD patients during treatment with Pio. 

Conclusions: Pio alters Mo/MΦ mitoROS/metabolism and efferocytic capability in human CGD as in murine CGD. PPARg agonism may be useful in reducing exaggerated inflammation in CGD and may restore some oxidant production in CGD phagocytes.