Macrophage-specific deletion of PPARγ impairs lung function and immune responses in an mouse model of Pseudomonas aeruginosa infection (INM8P.363)

• DOI: 10.4049/jimmunol.194.supp.195.7
• Publication Date: 2023-01-01T10:11:59Z
• Authors: Brenda Curtis; Jessica Palmer; Melissa Hoo; Mary Thomassen; Elizabeth Kovacs
• Keywords: 0301 basic medicine; 03 medical and health sciences; 3. Good health

Abstract Alveolar macrophages (AM) play a pivotal role in response to infection by first releasing pro-inflammatory molecules and phagocytosing pathogens and then resolving inflammation and clearing apoptotic neutrophils. This is accomplished largely based on their ability to switch from a pro-inflammatory to an anti-inflammatory phenotype. PPARγ is a transcription factor important for promoting resolution. To study the role of AM PPARγ in regulating respiratory function and immune responses in the context of bacterial infection, we utilized macrophage-specific PPARγ knockout mice (Mac PPARγ KO). Wild-type (C57Bl/6) or Mac PPARγ KO mice were given intratracheal Pseudomonas aeruginosa (40,000 CFU) or PBS control. After 24 hours, plethysmography was performed, followed by euthanasia. Compared to other groups, infected Mac PPARγ KO mice had impaired respiratory function, with a 5-fold increase in PenH (p<0.05) and a 50% reduction in minute volume and breath rate (p<0.05). Lungs of infected Mac PPARγ KO mice had dramatically increased cellularity, alveolar collapse, and interstitial thickening. Bacterial dissemination to the spleen was observed. Lastly, interleukin-6 levels were 40-fold higher in infected Mac PPARγ KO, compared to infected controls. Together, these findings suggest AM-specific PPARγ loss prolongs inflammation and weakens the ability to clear P. aeruginosainfection.