Transcriptional and Functional Diversity of Macrophage Repolarization: Implications in Chronic Inflammation and Cystic Fibrosis. Homo sapiens

Macrophage plasticity allows cells to adopt different phenotypes, a property with potentially important implications in chronic pulmonary disorders such as cystic fibrosis (CF). We examined the transcriptional and functional significance of macrophage repolarization from an “M1” (LPS-stimulated) towards an “M2” phenotype using 5 stimuli. We found that macrophages exhibit highly diverse responses to distinct M2-polarizing stimuli. Specifically, we observed that IL-10 abrogated LPS-tolerance allowing for rapid restoration of LPS responsiveness. In contrast, IL-4 enhanced LPS-tolerance, dampening pro-inflammatory responses after repeat LPS challenge. We found enrichment of phagocytosis-associated pathways in macrophages stimulated with IL-10, leading them to display the greatest efferocytosis ability. Finally, we observed that CF macrophages had intact reparative responses, suggesting that macrophage contributions to CF lung disease are shaped by their environmental milieu and are modifiable. These findings highlight the diversity of macrophage activation states, attribute functional consequences to these stimuli, and provide a unique resource of human macrophage repolarization markers. Overall design: Non-polarized, M0 state monocyte-derived macrophages (MDMs) from n= 6 cystic fibrosis (CF) patients and n =6 non-CF subjects were initially polarized to M1 by exposure to LPS. M1 MDMs were then cultured in MDM media alone (no treatment) or supplemented with IL-4, IL-10, methylprednisolone, azithromycin, or apoptotic PMNs for 24 h to repolarize MDMs towards an M2 state. Total RNA from each condition was isolated and hybridized to Illumina HumanHT-12 v4 BeadChip (total number of samples = 72).