Airway macrophages reveal their origins

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Science Translational Medicine  29 Jan 2020:
Vol. 12, Issue 528, eaba2915
DOI: 10.1126/scitranslmed.aba2915


Airway macrophages are derived from recipient circulating monocytes after transplant.

Airway macrophages (AMs) are important cell types in the lung, playing a pivotal role in host defense. Recent murine studies suggest that resident pulmonary macrophages self-maintain locally, with minimal contribution from circulating monocytes during health. The injured murine lung is known to contain two ontologically distinct AM populations, consisting of perinatally derived AMs and recruited circulating monocytes that transition into AM-like cells. However, AM ontogeny, aging, and contribution to disease are understudied in the human lung, hampering strategies to target age-related chronic lung disease.

Byrne and colleagues investigated AM ontogeny in human lung during healthy aging and after transplant. They characterized the circulating monocyte pool and resident AM populations in bronchoalveolar lavage samples from the airways of healthy volunteers during early life, adulthood, and in older age. This revealed that the activation pattern of circulating classical monocytes (CM) throughout life was comparable to those found in the airways, suggesting ongoing recruitment to the lung from CM precursors. Notably, aging impacted CM populations, which increased from childhood to adulthood, then reduced in older age, suggesting that dynamic alterations in peripheral and airway innate immunity occur during one’s life span.

Since monocytes are known macrophage precursors, the authors questioned next the origin of AMs in the human lung. They performed single-cell RNA sequencing on airway inflammatory cells isolated from sex-mismatched lung transplant recipients. Quantification of AMs revealed that the majority of these cells were recipient-derived, with minimum contribution from donor organ macrophages. These findings support that the majority of AMs in the human lung after transplant are peripherally derived cells rather than resident AMs originating from the donor.

This study challenges the notion that prenatally derived AMs persist in the human lung over the course of a lifetime, highlighting the critical role of peripherally derived AMs in human lung health. The discovery that self-renewing AMs in the human lung are readily replaced from the peripheral circulating monocyte pool provides important evidence for the origin of AMs and informs the design of future macrophage-targeted therapies for the treatment of age-related chronic lung diseases.

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