CD116+ fetal precursors migrate to the perinatal lung and give rise to human alveolar macrophages

Abstract

Despite their importance in lung health and disease, it remains unknown how human alveolar macrophages develop early in life. Here we define the ontogeny of human alveolar macrophages from embryonic progenitors in vivo, using a humanized mouse model expressing human cytokines (MISTRG mice). We identified alveolar macrophage progenitors in human fetal liver that expressed the GM-CSF receptor CD116 and the transcription factor MYB. Transplantation experiments in MISTRG mice established a precursor–product relationship between CD34−CD116+ fetal liver cells and human alveolar macrophages in vivo. Moreover, we discovered circulating CD116+CD64−CD115+ macrophage precursors that migrated from the liver to the lung. Similar precursors were present in human fetal lung and expressed the chemokine receptor CX3CR1. Fetal CD116+CD64− macrophage precursors had a proliferative gene signature, outcompeted adult precursors in occupying the perinatal alveolar niche, and developed into functional alveolar macrophages. The discovery of the fetal alveolar macrophage progenitor advances our understanding of human macrophage origin and ontogeny.

Mucosal immune responses to infection and vaccination in the respiratory tract

“…AMs are a unique subset of self-renewing, long-lived, lung-tissue-resident immune cells derived from the fetal liver and seeded early in the perinatal lung by CD116 + precursors ( Guilliams et al., 2013 ; Tan and Krasnow, 2016 ; Saluzzo et al., 2017 ; Evren et al., 2022 ). These cells are found in alveolar spaces where they moderate lipid homeostasis, facilitate gas exchange, and regulate surfactant catabolism ( Todd et al., 2016 ) ( Figure 1 A).…”

The innate immune brakes of the lung

“…Both subsets have been described in the human lung. Many similarities between mouse and human macrophages have been reported based on marker expression, location, function and even developmental pathway, especially for AMs, the most studied lung macrophages (19,20,28,29).…”

Tissue-resident immunity in the lung: a first-line defense at the environmental interface

“…1 Location of immune tissue-resident cells in the lungs (alveoli and bronchus). Created with BioRender.com temporal and tissue state-dependent origin of human AM was recently provided by Evren et al who characterized the embryonic origin of AM and pinpointed CD116 + fetal liver cells as human AM precursors in early life and steady-state conditions [26].…”