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

作者：Dalrymple Heidi; Barna Barbara P; Malur Anagha; Malur Achut G; Kavuru Mani S; Thomassen Mary Jane^*

来源：BMC Immunology, 2013, 14(1): 41.

DOI：10.1186/1471-2172-14-41

• Interferon gamma
• Activin A
• Alveolar macrophages

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 gamma). %26lt;br%26gt;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 gamma, a potent inducer of the M1 macrophage phenotype, in GM-CSF knockout BAL cells. IFN gamma mRNA was not elevated in PAP BAL cells. In vitro studies confirmed that IFN gamma stimulated activin A in wild-type AMs while antibody to IFN gamma reduced activin A in GM-CSF knockout AMs. Both IFN gamma and Activin A were also reduced in GM-CSF knockout mice in vivo after intratracheal instillation of lentivirus-PPAR gamma compared to control lentivirus vector. Examination of other M1 markers in GM-CSF knockout mice indicated intrinsic elevation of the IFN gamma-regulated gene, inducible Nitrogen Oxide Synthetase (iNOS), CCL5, and interleukin (IL)-6 compared to wildtype. The M2 markers, IL-10 and CCL2 were also intrinsically elevated. %26lt;br%26gt;Conclusions: Data point to IFN gamma as the primary upregulator of activin A in GM-CSF knockout mice which in addition, exhibit a unique mix of M1-M2 macrophage phenotypes.

• 出版日期2013-9-17