Alveolar macrophages of GM-CSF knockout mice exhibit mixed M1 and M2 phenotypes

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

Barbara P Barna (Creator)

Heidi Dalrymple (Creator)

Mani S Kavuru (Creator)

Anagha Malur (Creator)

Achut G Malur (Creator)

Mary Jane Thomassen (Creator)

Institution

East Carolina University (ECU )

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

Abstract: Background Activin A is a pleiotrophic regulatory cytokine, the ablation of which is neonatal lethal. Healthy human alveolar macrophages (AMs) constitutively express activin A, but AMs of patients with pulmonary alveolar proteinosis (PAP) are deficient in activin A. PAP is an autoimmune lung disease characterized by neutralizing autoantibodies to Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF). Activin A can be stimulated, however, by GM-CSF treatment of AMs in vitro. To further explore pulmonary activin A regulation, we examined AMs in bronchoalveolar lavage (BAL) from wild-type C57BL/6 compared to GM-CSF knockout mice which exhibit a PAP-like histopathology. Both human PAP and mouse GM-CSF knockout AMs are deficient in the transcription factor, peroxisome proliferator activated receptor gamma (PPAR?). Results In sharp contrast to human PAP, activin A mRNA was elevated in mouse GM-CSF knockout AMs, and activin A protein was increased in BAL fluid. Investigation of potential causative factors for activin A upregulation revealed intrinsic overexpression of IFN?, a potent inducer of the M1 macrophage phenotype, in GM-CSF knockout BAL cells. IFN? mRNA was not elevated in PAP BAL cells. In vitro studies confirmed that IFN? stimulated activin A in wild-type AMs while antibody to IFN? reduced activin A in GM-CSF knockout AMs. Both IFN? and Activin A were also reduced in GM-CSF knockout mice in vivo after intratracheal instillation of lentivirus-PPAR? compared to control lentivirus vector. Examination of other M1 markers in GM-CSF knockout mice indicated intrinsic elevation of the IFN?-regulated gene, inducible Nitrogen Oxide Synthetase (iNOS), CCL5, and interleukin (IL)-6 compared to wild-type. The M2 markers, IL-10 and CCL2 were also intrinsically elevated. Conclusions Data point to IFN? as the primary upregulator of activin A in GM-CSF knockout mice which in addition, exhibit a unique mix of M1-M2 macrophage phenotypes.

Additional Information

Publication

Other

BMC Immunology; 14: p. 41-41

Language: English

Date: 2013

Keywords

Alveolar macrophages, Interferon gamma, Activin A

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