Alterations in immune response and PPAR/LXR regulation in cystic fibrosis macrophages☆☆☆

Abstract 

Background

Cystic fibrosis (CF) is characterized by an excessive inflammatory response in epithelial cells and macrophages. In CF mice, lung inflammation can be abrogated by oral treatment with docosahexaenoic acid (DHA). Since PPARs and LXRs are important regulators of inflammation and fatty acid metabolism in macrophages, we hypothesized that these pathways are dysregulated in CF macrophages and are corrected with DHA treatment.

Methods

Peritoneal macrophages were obtained from wild type and cftr^−/− mice. LPS induced cytokine secretion and NFκB activity were analyzed with and without oral DHA treatment. The expression and activity of PPARα,γ, δ and LXRα were analyzed by RT-PCR and EMSA.

Results

LPS induced TNFα and IL-6 secretion and NFκB p65 activity were increased in CF macrophages. This was associated with low basal PPARγ expression and attenuated LPS induced induction of PPARδ, LXRα and ABCA1. DHA pretreatment in vivo decreased TNFα secretion and p65 activity, and increased PPARα and γ expression and function. The effects of DHA could be reproduced by PPAR agonists and blocked by a PPARα antagonist.

Conclusion

Impaired regulation of nuclear receptors may contribute to the abnormal LPS induced signaling in CF macrophages and is reversed by DHA.

Keywords: Cystic fibrosis mice, Nuclear receptors, Macrophages, Inflammation, Docosahexaenoic acid, Cytokines