Systemic Analysis of PPARγ in Mouse Macrophage Populations Reveals Marked Diversity in Expression with Critical Roles in Resolution of Inflammation and Airway Immunity

Although peroxisome proliferator-activated receptor gamma (PPAR gamma) has anti-inflammatory actions in macrophages, which macrophage populations express PPAR gamma in vivo and how it regulates tissue homeostasis in the steady state and during inflammation remains unclear. We now show that lung and spleen macrophages selectively expressed PPAR gamma among resting tissue macrophages. In addition, Ly-6C(hi) monocytes recruited to an inflammatory site induced PPAR gamma as they differentiated to macrophages. When PPAR gamma was absent in Ly-6C(hi)-derived inflammatory macrophages, initiation of the inflammatory response was unaffected, but full resolution of inflammation failed, leading to chronic leukocyte recruitment. Conversely, PPAR gamma activation favored resolution of inflammation in a macrophage PPAR gamma-dependent manner. In the steady state, PPAR gamma deficiency in red pulp macrophages did not induce overt inflammation in the spleen. By contrast, PPAR gamma deletion in lung macrophages induced mild pulmonary inflammation at the steady state and surprisingly precipitated mortality upon infection with Streptococcus pneumoniae. This accelerated mortality was associated with impaired bacterial clearance and inability to sustain macrophages locally. Overall, we uncovered critical roles for macrophage PPAR gamma in promoting resolution of inflammation and maintaining functionality in lung macrophages where it plays a pivotal role in supporting pulmonary host defense. In addition, this work identifies specific macrophage populations as potential targets for the anti-inflammatory actions of PPAR gamma agonists. The Journal of Immunology, 2012, 189: 2614-2624.