Identification of a functional GM-CSF / activin A / PPAR axis in human macrophages

The Myeloid Cell Biology group led by Dr. Ángel Corbí at Centro de Investigaciones Biológicas, is actively involved in determining the molecular mechanisms underlying the acquisition of pro-inflammatory and anti-inflammatory functions by human macrophages. Now, they have demonstrated that the PPARγ transcription factor is regulated by activin A and shapes the transcriptional signature of human alveolar macrophages.

Macrophages link the innate and adaptive branches of immune response and control the initiation and resolution of inflammatory responses, being capable of exerting either pro-inflammatory or anti-inflammatory functions. As a consequence, both exacerbated and defective functions of macrophages contribute to the onset and maintenance of clinically relevant chronic inflammatory diseases like obesity, atherosclerosis and cancer. As a way to keep their tissue-damaging actions in check, macrophages contain molecular brakes that impede their continuous secretion of pro-inflammatory molecules. The PPARγ transcription factor, which determines the acquisition of the metabolic-disease-specific phenotype of macrophages, is one of these molecular brakes, as it limits the macrophage pro-inflammatory activation.

Nieto and coworkers have shown, in a work recently published in the journal Frontiers of Immunology, how PPARγ is preferentially expressed by human macrophages generated under the influence of the Granulocyte-macrophage colony-stimulating factor (GM-CSF), and that the activity of PPARγ differs between pro-inflammatory and anti-inflammatory macrophages. Using siRNA-mediated knockdown strategies and global transcriptomic analysis, the authors have demonstrated that PPARγ significantly shapes the transcriptome of human pro-inflammatory and alveolar macrophages, promoting the downregulation of pro-inflammatory genes and altering the expression of genes involved in cell proliferation, migration and pathogen recognition. Besides, the work carried out at the Myeloid Cell Biology Laboratory has demonstrated that the macrophage PPARγ expression is determined by activin A, a soluble factor of the transforming growth factor beta (TGFß) family.

As a whole, the report indicates the existence of a functional GM-CSF/activin A/ PPARγ axis in human macrophages, and illustrates how PPARγ helps macrophages to switch from a pro-inflammatory to an anti-inflammatory state, what might contribute to limiting tissue damage and restoring homeostasis during inflammatory responses.

In addition, and from the pathology point of view, the finding by Nieto and coworkers is especially relevant because the absence of either GM-CSF or PPARγ in human alveolar macrophages results in a disease known as pulmonary alveolar proteinosis (PAP), where activin A levels are also defective. The identification of the GM-CSF/activin A/ PPARγ axis, together with the determination of the PPAR-dependent transcriptome in human macrophages, might help in the development of macrophage re-programming protocols for chronic inflammatory pathologies and even contribute to the design of therapeutic strategies for PAP.

Reference: The Activin A-Peroxisome Proliferator-Activated Receptor Gamma Axis Contributes to the Transcriptome of GM-CSF-Conditioned Human Macrophages. Nieto C, Bragado R, Municio C, Sierra-Filardi E, Alonso B, Escribese MM, Domínguez-Andrés J, Ardavín C, Castrillo A, Vega MA, Puig-Kröger A, Corbí AL. Front Immunol. 2018 Jan 29;9:31. doi: 10.3389/fimmu.2018.00031. eCollection 2018.