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Review
. 2020 Oct;41(10):864-877.
doi: 10.1016/j.it.2020.08.008. Epub 2020 Sep 4.

Teaching Old Dogs New Tricks? The Plasticity of Lung Alveolar Macrophage Subsets

Affiliations
Review

Teaching Old Dogs New Tricks? The Plasticity of Lung Alveolar Macrophage Subsets

Justina Kulikauskaite et al. Trends Immunol. 2020 Oct.

Abstract

Alveolar macrophages (AMs) are highly abundant lung cells with important roles in homeostasis and immunity. Their function influences the outcome of lung infections, lung cancer, and chronic inflammatory disease. Recent findings reveal functional heterogeneity of AMs. Following lung insult, resident AMs can either remain unchanged, acquire new functionality, or be replaced by monocyte-derived AMs. Evidence from mouse models correlates AM function with their embryonic or monocyte origin. We hypothesize that resident AMs are terminally differentiated cells with low responsiveness and limited plasticity, while recruited, monocyte-derived AMs are initially highly immunoreactive but more plastic, able to change their function in response to environmental cues. Understanding cell-intrinsic and -extrinsic mechanisms determining AM function may provide opportunities for intervention in lung disease.

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Figures

Figure 1
Figure 1
Model of Changes in Alveolar Macrophage (AM) Phenotype in the Post-Insult Lung. AMs found in the post-insult lung (A,B) (e.g., in mice) can be profibrotic or immunoreactive, compared with the steady-state, immunosedated resident AMs that are responsible for homeostatic functions (C). This may be explained by (A) monocyte-derived AMs retaining functionality similar to that of monocytes [10] due to their recent recruitment; or by (B) innate training. (a) Resident AMs can be trained to develop a more immunoreactive phenotype [39,40]. Recruited AMs can change functionally as a result of innate training at various stages, including (b) as AMs in the lung, (c) as monocytes in the blood [43], and (d) as monocyte progenitors or (e) hematopoietic stem cells in the BM [44., 45., 46.]. (f) Monocyte-derived AMs can lose reactivity and become immunosedated [10] by anti-inflammatory signals from the uninflamed lung environment. This figure was created using BioRender (https://biorender.com/).
Figure 2
Figure 2
Model of Kinetics of Alveolar Macrophage (AM) Immunosedation in Different Mouse Lung Environments. In this model, the immunoreactivity of monocyte-derived AMs is determined by the lung environment and the duration spent in the lung. After lung insult or depletion of AMs, highly reactive monocytes are recruited into the lung and lose reactivity over time (immunosedation). In a non-inflamed lung (blue), the signals from the environment may be anti-inflammatory and therefore immunosedate these cells fast and efficiently, while activating stimuli are largely absent. In a still-inflamed lung environment (red), both pro- and anti-inflammatory signals may be present, leading to a slower rate of immunosedation. This might explain the comparably low immunoreactivity of monocyte-derived AMs after sterile depletion and the higher immunoreactivity for a longer time period following an inflammatory insult [10., 11., 12.,49]. This figure was created using BioRender (https://biorender.com/).
Figure 3
Figure 3
Model of How Signals in the Mouse Lung Shape Newly Recruited Alveolar Macrophages (AMs). The functionality of monocyte-derived AMs can be shaped by various signals in the lung environment, including colony-stimulating factors (CSFs) (GM-CSF and M-CSF) and transforming growth factor beta (TGF-β), acting in a paracrine or autocrine manner. In the lung, monocyte-derived AMs are exposed to different amounts of glucose and fatty acids, which, together with other stimuli, may establish over time the transition from an immunoreactive phenotype initially to the subsequent immunosedation of recruited AMs expressing the signature transcription factor peroxisome proliferator-activated receptor gamma (PPAR-γ). This figure was created using BioRender (https://biorender.com/).

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