If a secretion in the alveoli of the lungs is not cleared regularly, breathing difficulties may develop. In a study published in Science Immunology, a team led by Alexander Mildner and Achim Leutz has just explained the central role of the transcription factor C/EBPb in this process.

Gas exchange between the air we breathe and our blood takes place via the alveoli – tiny air sacs in our lungs. For this process to go smoothly, the epithelial cells in the alveoli produce a substance called “surfactant” which coats the alveoli like a film. This complex consists mainly of phospholipids and proteins and serves to reduce the surface tension of the alveoli. It also acts as a filter, reliably trapping bacteria and viruses that enter the lungs when we inhale.

Surfactant is secreted continuously, as the substance used is constantly broken down and eliminated by alveolar macrophages (AM) – trap cells on the alveoli. This process maintains the correct balance between the synthesis and elimination of surfactants, a state known as homeostasis. “But if it goes wrong, more and more secretions build up in the lungs, impairing breathing and increasing the risk of lung infections,” says Professor Alexander Mildner, former Heisenberg Fellow at the Max Delbrück Center and now group leader at the University of Turku. Mildner is the latest author of the study and has been researching macrophages for 20 years. “We wanted to know what prevents these lung phagocytes from functioning properly,” he explains. Surfactant overaccumulation can lead to pulmonary alveolar proteinosis (PAP) – a previously incurable disease which, in severe cases, requires regular flushing of patients’ lungs.

The crucial role of C/EBPb

The study was triggered by the discovery that alveolar macrophages cannot grow properly if they lack C/EBPb. Professor Achim Leutz has been studying the function of this transcription factor for many years. He directs the Cellular Differentiation and Tumorigenesis Laboratory at the MDC, which hosted Mildner’s independent research group. Other MDC researchers involved in the study included Dr. Uta Höpken and Dr. Darío Jesús Lupiáñez García. Thanks to molecular biology studies and animal experiments, the team was able to explain the role of C/EBPb. Their results have just been published in the journal Sciences Immunology.

We isolated alveolar macrophages from healthy mice and those lacking the C/EBPb gene and performed in vitro tests on these immune cells. We also performed various genome and transcriptome analyzes of freshly isolated cells.”

Dr Dorothea Dörr, lead author of the study

More specifically, the researcher studied the biological and molecular properties of AMs, ie their ability to absorb and metabolize lipids. While macrophages from healthy mice performed their tasks correctly, those extracted from genetically modified mice absorbed and stored a large part of the lipids but were unable to digest them. Instead, they swelled into so-called “foam cells” and quickly perished, redepositing ingested lipids. The same phenomenon has been observed by physicians treating PAP lung disease. Moreover, defective macrophages were found to be barely able to proliferate.

An important piece of the puzzle

Molecular analyzes further showed that another important gene – also a transcription factor – is down-regulated in mice lacking the C/EBPb gene: PPARg. When activated, it stimulates, among other things, the absorption of fatty acids and the differentiation of fat cells and macrophages in the body.

PAP lung disease is usually the result of problems in the cytokine GM-CSF signaling pathway, which stands for granulocyte-macrophage colony-stimulating factor. “We already knew that some essential functions of alveolar macrophages are controlled via the GM-CSF signaling pathway,” says Mildner. “Now we have found that C/EBPb-deficient macrophages show severe dysfunctions in the proliferation of these cells and the degradation of surfactant, causing PAP-like pathology in mice.” It therefore seems that C/EBPb is the missing regulatory link between the GM-CSF and PPARg signaling pathways. “It’s like a puzzle,” says Leutz. “If you put in a certain piece, other missing pieces are suddenly much easier to find.”

A key to understanding other diseases?

Macrophages may be the scavenger cells of the immune system, but they do more than just eliminate bacteria and viruses from our system. Each organ has its own specialized macrophages. In brain remodeling, for example, their job is to break down neurons and synapses that are no longer needed. If they do not perform this task correctly, diseases of the central nervous system can develop.

Faulty lipid metabolism is not only the root cause of PAP; it is also responsible for atherosclerosis, a serious vascular disease. During this disease, more and more fatty deposits accumulate on the walls of the arteries, where they are trapped by white blood cells such as macrophages. These macrophages ingest lipids but cannot break them down properly, so they swell and form plaques. If the plaques ever open, the fat inside leaks out and can form clots blocking the arteries, which can cause a stroke or heart attack.

“We believe that the signaling pathway we have shed light on could be important in many lipid-related diseases,” says Mildner. “So the question now is whether what we’ve learned from alveolar macrophages could also help us better understand atherosclerosis and morbid obesity (adiposity).”

As for PAP, a new treatment may now be on the horizon. Therapeutic agents capable of modulating PPARg are already known. If used in combination with a C/EBPb activating drug, it may be possible to restart the lipid metabolism of dysregulated alveolar macrophages.


Max Delbrück Center for Molecular Medicine of the Helmholtz Association

Journal reference:

Dorr, D. et al. (2022) C/EBPβ regulates lipid metabolism and Pparg 2 isoform expression in alveolar macrophages. Sciences Immunology. doi.org/10.1126/sciimmunol.abj0140.

Source link