If a secretion within the lungs’ alveoli just isn’t cleared frequently, respiratory difficulties can develop. In a study published in Science Immunology, a team led by Alexander Mildner and Achim Leutz has now explained the pivotal role of the transcription factor C/EBPb on this process.

The exchange of gases between the air we breathe and our blood takes place via alveoli – tiny air sacs in our lungs. For this process to run easily, the epithelial cells of the alveoli produce a substance called “surfactant” that covers the alveoli like a movie. This complex consists mainly of phospholipids and proteins and serves to cut back the surface tension of the alveoli. It also acts like a filter, reliably trapping bacteria and viruses that enter the lungs once we inhale.

Surfactant is repeatedly secreted, because the substance used is always being broken down and cleared away by alveolar macrophages (AMs) – scavenger cells on the alveoli. This process maintains the suitable balance between surfactant synthesis and disposal, a state referred to as homeostasis. “But when it goes awry, increasingly more of the secretion accumulates within the lungs, which impairs respiratory and increases the danger of lung infections,” explains Professor Alexander Mildner, a former Heisenberg fellow on the Max Delbrück Center and now a bunch leader on the University of Turku. Mildner is the last creator of the study and has been researching macrophages for 20 years. “We desired to know what prevents these pulmonary phagocytes from functioning properly,” he says. An overaccumulation of surfactant may end up in pulmonary alveolar proteinosis (PAP) – a hitherto incurable disease that, in severe cases, requires patients’ lungs to be frequently flushed.

The crucial role of C/EBPb

The study was triggered by the invention that alveolar macrophages cannot develop properly in the event that they lack C/EBPb. Professor Achim Leutz has been researching the function of this transcription factor for a few years. He’s head of the Cell Differentiation and Tumorigenesis Lab on the MDC, which hosted Mildner’s independent research group. Other MDC researchers involved within the study included Dr. Uta Höpken and Dr. Darío Jesús Lupiáñez García. Through molecular biological studies and animal experiments, the team was in a position to explain the role of C/EBPb. Their results have now been published within the journal Science Immunology.

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

Dr. Dorothea Dörr, study’s lead creator

Specifically, the researcher investigated the biological and molecular properties of AMs – i.e., how well they’re able to absorb and metabolize lipids. While the macrophages of healthy mice performed their tasks properly, those extracted from the genetically modified mice took up and stored a whole lot of the lipids but were unable to digest them. As a substitute, they swelled up into so-called “foam cells” and shortly perished, redepositing the ingested lipids. The identical phenomenon has been observed by doctors treating the lung disease PAP. As well as, the defective macrophages proved barely in a position to proliferate.

A crucial piece of the puzzle

Molecular analyses further showed that one other necessary gene – also a transcription factor – is downregulated in mice lacking the C/EBPb gene: PPARg. When activated, this stimulates, amongst other things, the uptake of fatty acids and the differentiation of fat cells and macrophages within the body.

The lung disease PAP is usually the results of problems within the signaling pathway of the cytokine GM-CSF, which stands for granulocyte-macrophage colony-stimulating factor. “We already knew that certain essential functions of alveolar macrophages are controlled via the GM-CSF signaling pathway,” says Mildner. “Now now we have found that macrophages deficient in C/EBPb show severe malfunctions within the proliferation of those cells and the degradation of surfactant, causing a PAP-like pathology in mice.” It seems, due to this fact, that C/EBPb is the missing regulatory link between the GM-CSF and PPARg signaling pathways. “It’s like a jigsaw puzzle,” explains Leutz. “In the event you put in a certain piece, other missing pieces are suddenly much easier to seek out.”

A key to understanding other diseases?

Macrophages will be the scavenger cells of the immune system, but they do excess of just clear bacteria and viruses out of our system. Every organ has its own specialized macrophages. In the reworking of the brain, for instance, they’ve the duty of breaking down neurons and synapses which might be now not needed. In the event that they don’t perform this task accurately, central nervous system diseases can develop.

Faulty lipid metabolism just isn’t only the foundation explanation for PAP; it’s also chargeable for atherosclerosis – a serious vascular disease. During this disease, increasingly more fat deposits accumulate on the artery partitions, where they’re trapped by white blood cells like macrophages. These macrophages ingest the lipids but cannot break them down properly, so that they swell and form plaques. If the plaques ever break open, the fat inside escapes and will form artery-blocking clots – which could cause a stroke or heart attack.

“We expect that the signaling pathway now we have make clear could possibly be necessary in lots of lipid-related diseases,” says Mildner. “So the query now is whether or not what we have learned from alveolar macrophages may additionally help us higher understand atherosclerosis and morbid obesity (adiposity).”

As for PAP, a recent treatment may now be on the horizon. There are already known therapeutic agents that may modulate PPARg. If used together with a C/EBPb-activating drug, it could be possible to kick-start the lipid metabolism of dysregulated alveolar macrophages.

Source:

Max Delbrück Center for Molecular Medicine within the Helmholtz Association

Journal reference:

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