How Lung Macrophages Develop May Have Role in Disease, Study Says

Usually, macrophages protect the lungs from attacks. But under certain conditions, lung macrophages can also contribute to severe lung diseases, like chronic obstructive pulmonary disease, or worsen coronavirus disease 2019 (COVID-19).

Research on the development of human lung macrophages has been limited. A new study describes how these immune cells develop and may contribute to severe lung diseases, including chronic obstructive pulmonary disease (COPD) and coronavirus disease 2019 (COVID-19).

The researchers, from Sweden’s Karolinska Institutet, said their findings could contribute to future treatments. The study was published in Immunity.

The structure of the lungs exposes them to viruses and bacteria from both the air and the blood. Usually, macrophages protect the lungs from attacks. But under certain conditions, lung macrophages can also contribute to severe lung diseases or worsen a virus attack.

Macrophages can have different origins and develop, among other things, from monocytes that are divided into different genetically determined main types. Two of these are "classical" CD14+ monocytes and "non-classical" CD16+ monocytes.

The study involved a model to study the development of lung macrophages directly in a living lung. This has been combined with a method to study gene activity in individual cells, RNA sequencing, and thereby discovered how blood monocytes become human lung macrophages.

"In our study, we show that classical monocytes migrate into airways and lung tissue and are converted into macrophages that protect the health and function of the lungs. We have also identified a special kind of monocyte, HLA-DRhi, which is an intermediate immune cell between a blood monocyte and an airway macrophage. These HLA-DRhi monocytes can leave the blood circulation and migrate into the lung tissue," said Tim Willinger, a researcher and associate professor at the Department of Medicine, Huddinge, Karolinska Institutet, in a statement.

The non-classical monocytes develop into macrophages in the many blood vessels of the lungs and do not migrate into the lung tissue.

"Certain macrophages in the lungs probably have a connection to a number of severe lung diseases. In respiratory infections, for example, monocytes in the lungs develop into macrophages, which combat viruses and bacteria. But a certain type of macrophage may also contribute to severe inflammation and infections," said the study's first author Elza Evren, a doctoral student on the team.

In an infection with the novel coronavirus, SARS-CoV-2, which causes COVID-19, researchers believe that protective, anti-inflammatory macrophages are replaced by pro-inflammatory lung macrophages from blood monocytes.

"The existence of these blood monocyte-derived macrophages has been shown in other studies to correlate with how severely ill a person becomes in COVID-19 and how extensive the damage to the lungs is. Patients with severe COVID-19 also have fewer HLA-DRhi monocytes in their blood, probably because they move away from the blood into the lungs. Given their important role in rapid inflammatory responses, our results indicate that future treatments should focus on inflammatory macrophages and monocytes to reduce lung damage and mortality from severe COVID-19," said Willinger.