Origin and ontogeny of lung macrophages: from mice to humans

Abstract

Macrophages are tissue-resident myeloid cells with essential roles in host defense, tissue repair, and organ homeostasis. The lung harbors a large number of macrophages that reside in alveoli. As a result of their strategic location, alveolar macrophages are critical sentinels of healthy lung function and barrier immunity. They phagocytose inhaled material and initiate protective immune responses to pathogens, while preventing excessive inflammatory responses and tissue damage. Apart from alveolar macrophages, other macrophage populations are found in the lung and recent single-cell RNA-sequencing studies indicate that lung macrophage heterogeneity is greater than previously appreciated. The cellular origin and development of mouse lung macrophages has been extensively studied, but little is known about the ontogeny of their human counterparts, despite the importance of macrophages for lung health. In this context, humanized mice (mice with a human immune system) can give new insights into the biology of human lung macrophages by allowing in vivo studies that are not possible in humans. In particular, we have created humanized mouse models that support the development of human lung macrophages in vivo. In this review, we will discuss the heterogeneity, development, and homeostasis of lung macrophages. Moreover, we will highlight the impact of age, the microbiota, and pathogen exposure on lung macrophage function. Altered macrophage function has been implicated in respiratory infections as well as in common allergic and inflammatory lung diseases. Therefore, understanding the functional heterogeneity and ontogeny of lung macrophages should help to develop future macrophage-based therapies for important lung diseases in humans.

Keywords: humanized mice; lung macrophages; ontogeny; origin; single-cell RNA-sequencing.

Figure 1

Heterogeneity of lung macrophages. Macrophages occupy distinct locations in the lung, which corresponds to a division of labor. Alveolar macrophages reside in the airways, where they promote barrier immunity and surfactant clearance. Alveolar macrophages depend on the cytokines granulocyte–macrophage colony‐stimulating factor (GM‐CSF) and transforming growth factor β (TGF‐β). Interstitial macrophages are located within the lung tissue. Studies in mice have revealed two different populations of interstitial macrophages: (i) LYVE‐1^high MHC Class II^low interstitial macrophages adjacent to blood vessels that are involved in wound healing and tissue repair. (ii) LYVE‐1^low MHC Class II^high interstitial macrophages found near neurons that are specialized in antigen presentation. Lung macrophages can derive either from embryonic precursors or from blood monocytes. Parts of the figure have been adapted from Servier Medical Art.

Figure 2

A model to study human lung macrophages in vivo. Humanized ‘MISTRG’ mice express the human proteins macrophage colony‐stimulating factor (M‐CSF), interleukin‐3 (IL‐3)/granulocyte–macrophage colony‐stimulating factor (GM‐CSF), signal‐regulatory protein α(SIRPα), and thrombopoietin (TPO) in the Rag2 ^−/− Il2rg ^−/− background. MISTRG mice support the development of human blood monocytes as well as human interstitial and alveolar macrophages after transplantation with CD34⁺ hematopoietic stem and progenitor cells. Parts of figure have been adapted from Servier Medical Art.

Figure 3

Factors regulating lung macrophage function. Environmental factors such as the gut and local lung microbiota as well as pathogen exposure over the lifetime of the host affect lung macrophage function. In addition, differences have been observed in macrophage function depending on the age and sex of the individual. By regulating the function of lung macrophages, these factors likely influence the susceptibility to lung diseases. Parts of figure have been adapted from Servier Medical Art.