New study reveals how immune cells in the lungs

From our first breath, our lungs are exposed to microorganisms, such as bacteria and viruses. Thanks to the immune cells in the lungs called macrophages, we are protected from most infections from a young age. In a new study published in the Journal of Experimental Medicine, researchers from Karolinska Institutet show how pulmonary macrophages develop; new discoveries that can help reduce organ damage and that are important for the continued development of important treatments for lung disease.

Lung macrophages begin to develop in humans from birth, when the lungs are first inflated with inhaled air. Despite the importance of pulmonary macrophages in the immune system, it was not previously known how they develop in humans, as in-vivo studies in humans are difficult to conduct.

However, using a model, researchers at the Karolinska Institutet have now been able to directly study the development of human macrophages in a living lung. In the study, it was discovered that pulmonary macrophages develop in two different ways.

“In the first type of development, pulmonary macrophages originate from precursor cells already present in the fetal liver,” says Tim Willinger, associate professor in the Huddinge Department of Medicine, Karolinska Institutet, who led the study. “After we are born, these precursor cells pass from the liver to the lungs via the bloodstream. In the lungs, they are then exposed to various growth factors, which helps them develop into “mature” pulmonary macrophages. The second type of development occurs later in life. At this point, they develop from adult precursor cells, called monocytes, which are found in the blood.

Similar gene expression but different functions

The researchers also investigated whether the origin of pulmonary macrophages affects their function. Here, they could see that pulmonary macrophages, regardless of their origin, had similar gene expression but with different functions.

“We found that fetal precursor cells divide faster than adult precursor cells,” said Elza Evren, lead author of the study, a doctoral candidate in Tim Willinger’s research group. “Fetal precursor cells therefore populate the lungs more quickly, which is important early in life to quickly eliminate microorganisms and other inhaled particles. “

Rather, pulmonary macrophages derived from adult precursor cells have been shown to be strongly activated by interferon, a protein that works to defend against viral infections. It is therefore very likely that this particular type of pulmonary macrophage has an important function within the immune system to help fight viruses.

Researchers were also able to see that these pulmonary macrophages are similar to pro-inflammatory macrophages, which can become overactivated and contribute to severe lung damage in diseases such as COVID-19.

Limit lung damage and promote new treatments

The new findings contribute to a better understanding of the origin and function of pulmonary macrophages. The human fetal progenitor cell the researchers have identified is a potential cell that can be targeted to regenerate tissue-protective macrophages, limit organ damage, and promote tissue repair in an injured lung. These findings may also support the development of new treatments for a number of lung diseases.

The study was funded by grants from the Swedish Research Council, SciLifeLab, Knut and Alice Wallenberg Foundation, Karolinska Institute, Center for Innovative Medicine (CIMED), Stockholm region, Swedish Heart and Lung Foundation, Petrus och Augusta Hedlunds Stiftelse and the Royal Swedish Academy. Sciences. One of the authors from Yale University pointed out conflicts of interest, which are described in detail in the scientific article.

Publication: “CD116 + fetal precursors migrate to the perinatal lung and give rise to human alveolar macrophages”, Elza Evren, Emma Ringqvist, Jean-Marc Doisne, Anna Thaller, Natalie Sleiers, Richard A. Flavell, James P. Di Santo, Tim Willinger . Journal of Experimental Medicine, January 12, 2022, doi: 10.1084 / jem.20210987.

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