Obesity Inhibits Alveolar Macrophage Responses to Pseudomonas aeruginosa Pneumonia via Upregulation of Prostaglandin E₂ in Male, but Not Female, Mice

Obesity is associated with increased morbidity and mortality during bacterial pneumonia. Cyclooxygenase-2 (COX-2) and PGE₂ have been shown to be upregulated in patients who are obese. In this study, we investigated the role of obesity and PGE₂ in bacterial pneumonia and how inhibition of PGE₂ improves antibacterial functions of macrophages. C57BL/6J male and female mice were fed either a normal diet (ND) or high-fat diet (HFD) for 16 wk. After this time, animals were infected with Pseudomonas aeruginosa in the lung. In uninfected animals, alveolar macrophages were extracted for either RNA analysis or to be cultured ex vivo for functional analysis. HFD resulted in changes in immune cell numbers in both noninfected and infected animals. HFD animals had increased bacterial burden compared with ND animals; however, male HFD animals had higher bacterial burden compared with HFD females. Alveolar macrophages from HFD males had decreased ability to phagocytize and kill bacteria and were shown to have increased cyclooxygenase-2 and PGE₂. Treating male, but not female, alveolar macrophages with PGE₂ leads to increases in cAMP and decreased bacterial phagocytosis. Treatment with lumiracoxib-conjugated nanocarriers targeting alveolar macrophages improves bacterial phagocytosis and clearance in both ND and HFD male animals. Our study highlights that obesity leads to worse morbidity during bacterial pneumonia in male mice because of elevated PGE₂. In addition, we uncover a sex difference in both obesity and infection, because females produce high basal PGE₂ but because of a failure to signal via cAMP do not display impaired phagocytosis.