Researchers identify genetic defect in alveolar macrophages that causes lung disease

New discovery of the causes of PAP lung disease could also offer solutions for treating obesity and heart disease. The research group of Assistant Professor Alexander Mildner at the University of Turku in Finland has identified a genetic defect that causes fat accumulation in the alveoli.

Alveoli are small, bubble-like air sacs at the end of the bronchial tubes. They are vital for survival because they replace oxygen with carbon dioxide.

The alveoli are covered by a thin liquid membrane called a surfactant, which is composed primarily of lipids. The surfactant not only protects the lungs from airborne pathogens and dust, but also facilitates proper breathing by reducing alveolar surface tension.

Surfactant lipids are constantly produced and removed from the alveoli. Alveolar macrophages, the immune-scavenging cells in the lungs, degrade and recycle surface lipids. Defects in the development and function of alveolar macrophages lead to disruption of surfactant balance and pathological accumulation of surface lipids that ultimately clog the alveolar space. The accumulated fat makes the connectives swollen and foamy.

“We can observe this phenomenon in patients with pulmonary alveolar proteinosis (PAP). They have shortness of breath, impaired respiratory function and an increased risk of lung infections. It is a relatively rare disease,” says Associate Professor Alexander Mildner of InFLAMES Flagship at the University of Turku, Finland, who led the research in collaboration with Professor Achim Lutz’s group at the Max Delbrück Center in Berlin, Germany.

Macrophages lack essential cellular tools

A disorder in the regulation of genes leads to a defect in the macrophages. One such disorder had already been identified, but Mildner and his group discovered that the absence of a second regulator renders macrophages unable to remove the lipids in the surfactant.

This regulatory gene is the transcription factor C/EBPb. We observed that C/EBPb-deficient macrophages lack the necessary cellular tools to remove lipids.”

Alexander Mildner, Associate Professor, University of Turku, Finland

The significance of the new finding is not limited to PAP disease alone. Foamy macrophages are also found in people with obesity or atherosclerosis.

“Perhaps we can learn from the alveolar macrophages in the lungs and translate our findings to other macrophages and help them digest lipids more efficiently. In the future, it may be possible to pharmacologically activate the C/EBPb-Pparg2 macrophage network in patients with obesity. Or PAP. or atherosclerosis and enhance fat digestion in these cells. This could provide new strategies for treating these patients,” says Mildner.

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Journal reference:

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