If the secretions from the alveoli are not cleared regularly, breathing difficulties may occur. In a study published in Science Immunology, a team led by Alexander Mildner and Achim Leutz has now elucidated the pivotal role of the transcription factor C/EBPb in this process.
Gases are exchanged between the air we breathe and our blood through the alveoli – the tiny air sacs in our lungs. For this process to go smoothly, the alveolar epithelial cells produce a substance called “surfactant” that coats the alveoli like flakes. This compound consists mainly of phospholipids and proteins and works to reduce the surface tension of the alveoli. It also acts as a filter, trapping bacteria and viruses that enter the lungs when we inhale.
Surfactant is constantly secreted, as the constantly used substance is broken down and eliminated by alveolar macrophages (AMs) – scavenging cells of the alveoli. This process maintains the right balance between surfactant synthesis and disposal, a condition known as homeostasis. Explains Professor Alexander Mildner, a former Heisenberg Fellow at the Max Delbrück Center and now a group leader at the University of Turku. Mildner is the latest author of the study and has been looking for macrophages for 20 years. “We wanted to know what prevents these pulmonary phagocytes from working properly,” he says. The accumulation of surfactant can lead to pulmonary alveolar proteinosis (PAP) – a hitherto incurable disease that, in severe cases, requires regular cleaning of patients’ lungs.
The critical role of C/EBPb
The study was launched by the discovery that alveolar macrophages cannot develop properly if they lack C/EBPb. Professor Achim Lutz has been searching for the function of this transcription factor for many years. He is head of the Laboratory for Cellular Differentiation and Oncogenesis at the Center for Bone Development, which hosted the Mildner independent research group. Other MDC researchers involved in the study included Dr. Uta Hopkin and Dr. Dario Jesus Lópeanez García. Through molecular biological studies and animal experiments, the team was able to explain the role of C/EBPb. Their results have now been published in the journal Immunology.
We isolated alveolar macrophages from healthy mice and from those lacking the gene for C/EBPb and performed in the laboratory Tests on these immune cells. We also performed several genome and transcriptome analyzes of the freshly isolated cells.”
Dr Dorothea Dorr, lead author of the study
Specifically, the researcher investigated the biological and molecular properties of AMs–that is, their ability to absorb and metabolize lipids. While the healthy mice’s macrophages functioned properly, those from the genetically modified mice took in and stored a lot of fat but were unable to digest it. Instead, they swelled up to become so-called “foam cells” and quickly perished, re-deposition of the ingested fat. The same phenomenon has been observed by doctors who treat chronic bronchitis. In addition, defective macrophages proved to be barely able to reproduce.
An important piece of the puzzle
Molecular analyzes further demonstrated that another important gene – also a transcription factor – is upregulated in mice lacking the C/EBPb gene: PPARg. When activated, this stimulates, among other things, the uptake 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 GM-CSF cytokine signaling pathway, which is the colony-stimulating factor of granulocytes. “We already knew that some basic functions of alveolar macrophages are controlled via the GM-CSF signaling pathway,” Mildner says. “We have now found that macrophages deficient in C/EBPb exhibit severe abnormalities in the proliferation of these cells and degradation of surfactant, causing PAP-like diseases in mice.” Therefore, C/EBPb appears to be the missing regulatory link between the GM-CSF and PPARg signaling pathways. “It’s like a jigsaw puzzle,” explains Leutz. “If you put down a particular piece, it will be much easier to find the other missing pieces.”
A key to understanding other diseases?
Macrophages may be the scavenger cells of the immune system, but they do much more than simply remove bacteria and viruses from our system. Each organ has its own specialized macrophages. In brain remodeling, for example, they have the task of breaking 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.
Improper fat metabolism is not only the root cause of PAP; It is also responsible for atherosclerosis – a dangerous disease of the blood vessels. 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 fat but cannot break it down properly, so it swells and forms plaques. If at any point the plaques open, the fat inside them leaks out and may form arterial clots — which can cause a stroke or heart attack.
“We think the signaling pathway that we’ve highlighted could be important in many fat-related diseases,” Mildner says. “So the question now is whether what we learned from alveolar macrophages may also help us better understand atherosclerosis and pathological obesity (obesity).
As for PAP, a new treatment may now be on the horizon. There are already known therapeutic agents that can modulate PPARg. If used in combination with a C/EBPb activator drug, it may be possible to initiate lipid metabolism in disorganized alveolar macrophages.
role, d. et al. (2022) C/EBPβ regulates lipid metabolism and Pparg isoform 2 expression in alveolar macrophages. Immunology. doi.org/10.1126/sciimmunol.abj0140.