| First Author | Fernandez-Boyanapalli R | Year | 2010 |
| Journal | Blood | Volume | 116 |
| Issue | 22 | Pages | 4512-22 |
| PubMed ID | 20693431 | Mgi Jnum | J:166653 |
| Mgi Id | MGI:4848290 | Doi | 10.1182/blood-2010-02-272005 |
| Citation | Fernandez-Boyanapalli R, et al. (2010) PPARgamma activation normalizes resolution of acute sterile inflammation in murine chronic granulomatous disease. Blood 116(22):4512-22 |
| abstractText | Absence of a functional nicotinamide adenine dinucleotide phosphate (NADPH) oxidase predisposes chronic granulomatous disease (CGD) patients to infection, and also to unexplained, exaggerated inflammation. The impaired recognition and removal (efferocytosis) of apoptotic neutrophils by CGD macrophages may contribute to this effect. We hypothesized that peroxisome proliferator-activated receptor gamma (PPARgamma) activation during CGD inflammation is deficient, leading to altered macrophage programming and decreased efferocytosis, and that PPARgamma agonism would enhance resolution. using the gp91(phox-/-) murine model of X-linked CGD in a well-characterized model of sterile, zymosan-induced peritonitis, it was demonstrated that PPARgamma expression and activation in CGD macrophages were significantly deficient at baseline, and acquisition was delayed over the course of inflammation relative to that of wild-type. Efferocytosis by macrophages reflected PPARgamma activation during peritonitis and was impaired in CGD mice (versus wild-type), leading to accumulation of apoptotic neutrophils. Importantly, provision of the PPARgamma agonist, pioglitazone, either prophylactically or during inflammation, significantly enhanced macrophage PPARgamma-mediated programming and efferocytosis, reduced accumulation of apoptotic neutrophils, and normalized the course of peritonitis in CGD mice. As such, PPARgamma may be a therapeutic target for CGD, and possibly other inflammatory conditions where aberrant macrophage programming and impaired efferocytosis delay resolution of inflammation. |
