Team Identifies Macrophage Defect Underlying Pulmonary Alveolar Proteinosis

Researchers in Finland have uncovered a developmental defect in alveolar macrophages that causes pulmonary alveolar proteinosis (PAP), a relatively rare condition that can leave sufferers susceptible to lung diseases and even lead to death. The findings have implications for PAP research as well as other disorders related to defective macrophages.

Pulmonary alveoli—the tiny bubble-like air sacs at the end of bronchial tubes—are vital for survival as they exchange oxygen for carbon dioxide.  They are covered by a thin fluid film called surfactant that consists mainly of lipids. This surfactant not only protects the lungs against airborne pathogens and dust, but also facilitates proper respiration by reducing the alveolar surface tension.  Surfactant lipids are constantly produced and cleared from the alveoli by alveolar macrophages, the immune scavenger cells of the lungs. However, defects in the development and function of alveolar macrophages lead to a disturbed surfactant balance and a pathological accumulation of surfactant lipids that ultimately clogs the alveolar space. The accumulated lipids also make the macrophages bloated and foamy.  

"We can observe this phenomenon in patients with [PAP]. They suffer from shortness of breath, an impaired respiratory function and an increased risk of lung infections," says Associate Professor Alexander Mildner from the InFLAMES Flagship Programme at the University of Turku, Finland, who led the research in cooperation with Professor Achim Leutz group at the Max-Delbrück Center in Berlin, Germany.

The defective macrophages are the result of errors in gene regulation. One of these defects had already been identified, but Mildner and colleagues discovered that the lack of a second regulator makes the macrophages unable to clear the lipids in the surfactant. "This regulatory gene is the transcription factor C/EBPb. We observed that C/EBPb-deficient macrophages lacked the cellular tools required for the clearance of lipids," Mildner says.

The significance of the new discovery is not just limited to the PAP disease. Bloated, foamy macrophages are also found in people with obesity or atherosclerosis.    "Maybe we can learn from alveolar macrophages in the lungs and translate our findings to other macrophages and help them to digest lipids more effectively. In the future, it could be possible to pharmacologically activate the macrophage C/EBPb-Pparg2 network in patients with obesity, PAP or atherosclerosis and promote lipid digestion in these cells. This could provide new strategies to treat these patients," says Mildner.

The findings were published in the journal Science Immunology.