Peroxisome Proliferator-Activated Receptor-γ Regulates the Expression of Alveolar Macrophage Macrophage Colony- Stimulating Factor

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Susamma Abraham (Creator)

Tracey L. Bonfield (Creator)

Daniel A. Culver (Creator)

Carol F. Farver (Creator)

Mary T. Koloze (Creator)

David M. Mosser (Creator)

Mary Jane Thomassen (Creator)

Xia Zhang (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Macrophage CSF (M-CSF) regulates monocyte differentiation, activation, and foam cell formation. We have observed that it is elevated in human pulmonary alveolar proteinosis (PAP) and in the GMCSF knockout mouse, a murine model for PAP. A potential regulator of M-CSF, peroxisome proliferator-activated receptor-γ (PPARγ), is severely deficient in both human PAP and the GM-CSF knockout mouse. To investigate the role of PPARγ in alveolar macrophage homeostasis, we generated myeloidspecific PPARγ knockout mice using the Lys-Cre method to knock out the floxed PPARγ gene. Similar to the GM-CSF-deficient mouse, absence of alveolar macrophage PPARγ resulted in development of lung pathology resembling PAP in 16-wk-old mice, along with excess M-CSF gene expression and secretion. In ex vivo wild-type alveolar macrophages, we observed that M-CSF itself is capable of inducing foam cell formation similar to that seen in PAP. Overexpression of PPARγ prevented LPS-stimulated M-CSF production in RAW 264.7 cells, an effect that was abrogated by a specific PPARγ antagonist, GW9662. Use of proteasome inhibitor, MG-132 or a PPARγ agonist, pioglitazone, prevented LPS-mediated M-CSF induction. Using chromatin immunoprecipitation, we found that PPARγ is capable of regulating M-CSF through transrepression of NF-κB binding at the promoter. Gel-shift assay experiments confirmed that pioglitazone is capable of blocking NF-κB binding. Taken together, these data suggest that M-CSF is an important mediator of alveolar macrophage homeostasis, and that transcriptional control of M-CSF production is regulated by NF-κB and PPARγ.

Additional Information

Publication

Other

Journal of Immunology\; 181:1 p. 235-242

Language: English

Date: 2023

Subjects

Macrophage CSF;Peroxisome;Pulmonary alveolar proteinosis

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