04:38pm Thursday 19 October 2017

New clues to the developmental origin of alveolar macrophages

Could you explain the controversies surrounding the development of AMFs?
Martin: For a long time macrophages were thought to derive continuously from adult monocytes.
This was based on the fact that adult monocytes can be differentiated into macrophages in vitro.
During my previous postdoc, I demonstrated that this model applied to intestinal macrophages. But
in 2012, in Science, Frederic Geissmann (King’s College London) proposed that most tissueresident
macrophages develop before birth from yolk-sac-derived macrophages. It was therefore unknown where AMFs come from.

 

How did you investigate the ontogeny of AMFs?
Initially using flow cytometry, we identified two potential precursor cells that colonized the developing lung before birth: fetal macrophages originating from the yolk sac and fetal monocytes
originating from the fetal liver. To identify which of these precursors developed into AMFs, we
then sorted both fetal macrophages and fetal monocytes and transferred them into newborn mice. This allowed us to demonstrate that fetal monocytes developed into AMFs within one week but also that these cells were indeed extremely long-lived as the transferred fetal monocytes could be found as AMFs in adult mice several months after transfer. Finally, we could demonstrate that GM-CSF plays a crucial role in this process.

 

What is the impact of these findings?
On the one hand, we provide a third model for macrophage development. It now remains to be investigated whether other tissue-resident macrophages follow Geissmann’s yolk sac macrophage model, the intestinal macrophage model (adult monocyte origin) or the AMF model we have  described here (i.e. fetal monocyte origin). On the other hand, we observed that the mice deficient for GM-CSF did not only lack AMFs but developed the clinical symptoms of pulmonary alveolar proteinosis (abbreviated PAP), a rare lung disease in which abnormal accumulation of surfactant occurs within the alveoli. Interestingly, PAP has been associated with mutations in the GM-CSF-receptor in patients, which suggests that our findings could be applicable to humans. We therefore hope that a better understanding of AMF differentiation might lead to novel treatments against PAP.

 

Guilliams, De Kleer et al.
JEM, 2013


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