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The Versatile Role of Alveolar Macrophages in Health and Disease International Journal of Molecular Sciences Review Beyond “Big Eaters”: The Versatile Role of Alveolar Macrophages in Health and Disease Miriam Hetzel 1,2, Mania Ackermann 1,2,3 and Nico Lachmann 2,3,4,5,* 1 Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany; [email protected] (M.H.); [email protected] (M.A.) 2 REBIRTH Research Center for Translational and Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany 3 Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, 30625 Hannover, Germany 4 Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), 30625 Hannover, Germany 5 Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, 30625 Hannover, Germany * Correspondence: [email protected] Abstract: Macrophages act as immune scavengers and are important cell types in the homeostasis of various tissues. Given the multiple roles of macrophages, these cells can also be found as tissue resident macrophages tightly integrated into a variety of tissues in which they fulfill crucial and organ-specific functions. The lung harbors at least two macrophage populations: interstitial and alveolar macrophages, which occupy different niches and functions. In this review, we provide the latest insights into the multiple roles of alveolar macrophages while unraveling the distinct factors which can influence the ontogeny and function of these cells. Furthermore, we will high- light pulmonary diseases, which are associated with dysfunctional macrophages, concentrating on Citation: Hetzel, M.; Ackermann, M.; congenital diseases as well as pulmonary infections and impairment of immunological pathways. Lachmann, N. Beyond “Big Eaters”: Moreover, we will provide an overview about different treatment approaches targeting macrophage The Versatile Role of Alveolar dysfunction. Improved knowledge of the role of macrophages in the onset of pulmonary diseases Macrophages in Health and Disease. may provide the basis for new pharmacological and/or cell-based immunotherapies and will extend Int. J. Mol. Sci. 2021, 22, 3308. our understanding to other macrophage-related disorders. https://doi.org/10.3390/ijms22073308 Keywords: alveolar macrophage; surfactant; pulmonary infections; asthma; fibrosis; tolerogenic po- Academic Editors: Malgorzata Kloc and Jacek Z Kubiak tential; pulmonary alveolar proteinosis; monocytes Received: 24 February 2021 Accepted: 20 March 2021 Published: 24 March 2021 1. Introduction Tissue resident macrophages (TRM) have recently been highlighted as key play- Publisher’s Note: MDPI stays neutral ers in the tissue homeostasis of various organs. Within the lung, several subsets of with regard to jurisdictional claims in macrophages exist, such as interstitial macrophages (IM) or alveolar macrophages (AM). In published maps and institutional affil- fact, nonalveolar IM are located primarily in the lung tissue around blood vessels or peri- iations. bronchial and significantly contribute to lung immune homeostasis and other tolerogenic cellular pathways. In contrast, the classical AM reside in the bronchioalveolar space and represent an important cell type in lung surfactant homeostasis, pulmonary host defense, and tissue tolerance (Figure1). In the alveolar space, AM are the best characterized and the Copyright: © 2021 by the authors. most abundant cell type and due to their crucial role direct impairment in both, function Licensee MDPI, Basel, Switzerland. and ontogeny of AM was noted to be important in the onset and progression of a variety This article is an open access article of lung diseases [1]. Of note, while IM also fulfil manifold important functions in lung distributed under the terms and homeostasis (as reviewed elsewhere [2]), we here focus on the contribution of AM to the conditions of the Creative Commons onset and progression of certain lung diseases. Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Int. J. Mol. Sci. 2021, 22, 3308. https://doi.org/10.3390/ijms22073308 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 25 stem cells (HSC). Studies in the murine system showed that erythro‐myeloid progenitors (EMP) give rise to premacrophages, which colonize the individual tissues, including the lung, before birth and give rise to TRM populations [3]. In the human system, recent in‐ sights suggest a similar developmental trajectory, which follows a spatiotemporal dy‐ namic of TRMs [4]. In the absence of inflammation and tissue damage, alveolar macro‐ phages are long lived and can self‐maintain their cell pool by local proliferation, with only minor contribution of adult monocytes over time. However, inflammatory processes can trigger the recruitment of monocytes to the lung, where they potentially participate in pathogenic processes. Under which circumstances these monocytes reside in the lungs and to which degree they finally resemble resident AMs is still under debate. In this con‐ text, the “niche model” suggests that strong triggers from the lung microenvironment im‐ Int. J. Mol. Sci. 2021, 22, 3308 print the AM phenotype on the infiltrating monocytes over time. Indeed, recent work2 by of 22 Evren and colleagues demonstrated that human monocytes are able to adopt an AM phe‐ notype over time and reside long‐term in the lung of immunodeficient mice [5]. FigureFigure 1. Impairment 1. Impairment of alveolar of alveolar macrophages macrophages leads leads to specific to specific diseases diseases or infections. or infections. Alveolar Alveolar macrophages macrophages (AM) (AM)are the are mostthe abundant most abundant cell type cell in type the inbronchioalveolar the bronchioalveolar space. space. Given Giventhe high the plasticity high plasticity of AM of and AM the and possibility the possibility to switch to switch be‐ tween different activation stages, alteration of AM can lead to a nonfunctional polarization/activation and subsequent between different activation stages, alteration of AM can lead to a nonfunctional polarization/activation and subsequent alterations in, e.g., maintaining tissue homeostasis (1). Furthermore, genetic and environmental factors can also influence alterations in, e.g., maintaining tissue homeostasis (1). Furthermore, genetic and environmental factors can also influence the antimicrobial function of AM, which can lead to life‐threatening pulmonary infections (e.g., bacterial airway infections) (2).the Dysfunction antimicrobial of AM function due ofto AM,genetic which mutations can lead or to other life-threatening factors can pulmonaryalso alter signaling infections pathways (e.g., bacterial (e.g., airwaythe CSF2 infections) path‐ way),(2). Dysfunctionwhich ultimately of AM can due lead to to genetic impaired mutations tissue homeostasis, or other factors e.g., can clearance also alter of signaling surfactant pathways material, (e.g., as seen the in CSF2 Pulmonary pathway), Alveolarwhich ultimatelyProteinosis can (3) (Created lead to impaired with BioRender.com). tissue homeostasis, e.g., clearance of surfactant material, as seen in Pulmonary Alveolar Proteinosis (3) (Created with BioRender.com). Genetic defects, environmental factors, drugs and other determinants can influence Under healthy, steady-state conditions, AM are predominantly derived from Myb- both the ontogeny and function of AM, leading to a variety of diseases. In fact, recent independent yolk sac progenitors, which develop before the emergence of hematopoietic research investigating the driving factors of patient’s susceptibility to pulmonary infec‐ stem cells (HSC). Studies in the murine system showed that erythro-myeloid progeni- tions proved that signaling pathways like GM‐CSF, or type I and/or II interferon signaling tors (EMP) give rise to premacrophages, which colonize the individual tissues, includ- can be responsible for impaired development and/or function of AM [6,7] (Figure 2). Fur‐ ing the lung, before birth and give rise to TRM populations [3]. In the human system, recent insights suggest a similar developmental trajectory, which follows a spatiotempo- ral dynamic of TRMs [4]. In the absence of inflammation and tissue damage, alveolar macrophages are long lived and can self-maintain their cell pool by local proliferation, with only minor contribution of adult monocytes over time. However, inflammatory pro- cesses can trigger the recruitment of monocytes to the lung, where they potentially par- ticipate in pathogenic processes. Under which circumstances these monocytes reside in the lungs and to which degree they finally resemble resident AMs is still under debate. In this context, the “niche model” suggests that strong triggers from the lung microenviron- ment imprint the AM phenotype on the infiltrating monocytes over time. Indeed, recent work by Evren and colleagues demonstrated that human monocytes are able to adopt an AM phenotype over time and reside long-term in the lung of immunodeficient mice [5]. Genetic defects, environmental factors, drugs and other determinants can influence both the ontogeny and function of AM, leading to a variety of diseases. In fact, recent re- search investigating the driving factors of patient’s susceptibility to pulmonary infections proved that signaling pathways like GM-CSF, or type I and/or II interferon signaling can Int. J. Mol. Sci. 2021, 22, 3308 3 of 22 Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 3 of 25 be responsible
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