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

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.

Leukocyte Function in COPD: Clinical Relevance and Potential for Drug Therapy

“…Within the alveolar compartment, alveolar macrophages have <5% proliferation capacity, 9 but whether this activity is sufficient to account for the increased numbers of macrophages in COPD is unknown. 10 In IPF there is accumulation of monocyte-derived macrophages (MDM) that are highly pro-inflammatory, 11 , 12 and it is likely that MDM contribute to much of the observed macrophage population found in COPD. 13 It is clear that the macrophage in COPD is dysfunctional and releases high levels of inflammatory mediators including CXCL8 and granulocyte macrophage-colony stimlating factor (GM-CSF); the latter is important in the context of macrophage development as it drives macrophage differentiation.…”

The Role of Macrophages During Mammalian Tissue Remodeling and Regeneration Under Infectious and Non-Infectious Conditions

“…Following influenza infection, monocyte-derived MФ are recruited to the lungs where they persist and over time, acquire hallmarks of tissue resident alveolar MФ where they participate in the replenishment of the alveolar MФ pool following resolution of acute infection. Interestingly, the monocyte-derived MФ transcriptomic profiles remain altered for several weeks after influenza infection, while tissue resident alveolar MФ are barely affected and, therefore, considered as "terminally sedated" (118,150,151). Given the importance of MФ on epithelial cell proliferation and differentiation, it is reasonable to assume that the effectiveness of lung tissue regeneration is dependent on the phenotype of both tissue resident and newly recruited monocytederived alveolar MФ.…”

How and to What Extent Immunological Responses to SARS-CoV-2 Shape Pulmonary Function in COVID-19 Patients

“…NK cells directly kill virally infected cells via their spontaneous cytolytic activity and activate the innate and adaptive immune system via secreting a variety of soluble mediators. Monocytes have specialized roles in the human lung ( Landsman et al, 2007 ; Bassler et al, 2019 ; Kulikauskaite and Wack, 2020 ). Tissue resident macrophages, such as alveolar macrophages (AM) of the lung play a major role in early innate immunity against infections and environmental challenges ( Kopf et al, 2015 ; Wynn and Vannella, 2016 ; Watanabe et al, 2019 ).…”