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Review
. 2021 Mar 24;22(7):3308.
doi: 10.3390/ijms22073308.

Beyond "Big Eaters": The Versatile Role of Alveolar Macrophages in Health and Disease

Miriam Hetzel  1   2 , Mania Ackermann  1   2   3 , Nico Lachmann  2   3   4   5
Affiliations
Review

Beyond "Big Eaters": The Versatile Role of Alveolar Macrophages in Health and Disease

Miriam Hetzel et al. Int J Mol Sci. .

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 highlight pulmonary diseases, which are associated with dysfunctional macrophages, concentrating on congenital diseases as well as pulmonary infections and impairment of immunological pathways. Moreover, we will provide an overview about different treatment approaches targeting macrophage dysfunction. Improved knowledge of the role of macrophages in the onset of pulmonary diseases may provide the basis for new pharmacological and/or cell-based immunotherapies and will extend our understanding to other macrophage-related disorders.

Keywords: alveolar macrophage; asthma; fibrosis; monocytes; pulmonary alveolar proteinosis; pulmonary infections; surfactant; tolerogenic potential.

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Conflict of interest statement

M.A. and N.L. are authors on a pending patent application: “Stem-cell derived myeloid cells, generation and use thereof”, PCT/EP2018/061574. M.H. declares no conflict of interest.

Figures

Figure 1
Figure 1
Impairment of alveolar macrophages leads to specific diseases or infections. Alveolar macrophages (AM) are the most abundant cell type in the bronchioalveolar space. Given the high plasticity of AM and the possibility to switch 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 the antimicrobial function of AM, which can lead to life-threatening pulmonary infections (e.g., bacterial airway infections) (2). Dysfunction of AM due to genetic mutations or other factors can also alter signaling pathways (e.g., the CSF2 pathway), which ultimately can lead to impaired tissue homeostasis, e.g., clearance of surfactant material, as seen in Pulmonary Alveolar Proteinosis (3) (Created with BioRender.com).
Figure 2
Figure 2
Genetic alterations causing impairment of alveolar macrophages in the context of pulmonary infection. Inborn errors in various genes can lead to alveolar macrophage dysfunction. (I) Following binding of GM-CSF, the CSF2R complex (CSF2RA/B) initiates downstream signaling by phosphorylation of STAT5 (pSTAT5) to activate important target genes such as SPI1 or PPARγ. Thus, mutations in either CSF2RA or CSF2RB lead to a block of GM-CSF signaling which can impair proper breakdown of bacteria. (II) Similarly, IFNγ activates the IFNgR1-IFNgR2 signaling complex and induces downstream phosphorylation of STAT1 (pSTAT1) and the subsequent activation of target genes such as members of the Interferon-regulatory factors (IRF) or iNOS. An impairment of this signaling cascade leads to the impaired clearance of mycobacterial infections and the clinical symptoms of Mendelian Susceptibility to Mycobacterial Disease. (III) Moreover, loss of function mutations in type-I interferon receptors (IFNAR1/R2) can impair the phosphorylation of STAT1 and 2 (pSTAT1/2) and their respective downstream signaling. This results in an increased susceptibility and decreased clearance capacity of macrophages against viral pathogens (Created with BioRender.com).
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