Human Lung Mononuclear Phagocytes in Health and Disease

Abstract

The lungs are vulnerable to attack by respiratory insults such as toxins, allergens, and pathogens, given their continuous exposure to the air we breathe. Our immune system has evolved to provide protection against an array of potential threats without causing collateral damage to the lung tissue. In order to swiftly detect invading pathogens, monocytes, macrophages, and dendritic cells (DCs)—together termed mononuclear phagocytes (MNPs)—line the respiratory tract with the key task of surveying the lung microenvironment in order to discriminate between harmless and harmful antigens and initiate immune responses when necessary. Each cell type excels at specific tasks: monocytes produce large amounts of cytokines, macrophages are highly phagocytic, whereas DCs excel at activating naïve T cells. Extensive studies in murine models have established a division of labor between the different populations of MNPs at steady state and during infection or inflammation. However, a translation of important findings in mice is only beginning to be explored in humans, given the challenge of working with rare cells in inaccessible human tissues. Important progress has been made in recent years on the phenotype and function of human lung MNPs. In addition to a substantial population of alveolar macrophages, three subsets of DCs have been identified in the human airways at steady state. More recently, monocyte-derived cells have also been described in healthy human lungs. Depending on the source of samples, such as lung tissue resections or bronchoalveolar lavage, the specific subsets of MNPs recovered may differ. This review provides an update on existing studies investigating human respiratory MNP populations during health and disease. Often, inflammatory MNPs are found to accumulate in the lungs of patients with pulmonary conditions. In respiratory infections or inflammatory diseases, this may contribute to disease severity, but in cancer patients this may improve clinical outcomes. By expanding on this knowledge, specific lung MNPs may be targeted or modulated in order to attain favorable responses that can improve preventive or treatment strategies against respiratory infections, lung cancer, or lung inflammatory diseases.

Airway macrophages as the guardians of tissue repair in the lung

“…AM originate from embryonic precursors and reside in the luminal niche postanatally . However, following injury or infection, the resident macrophage pool is rapidly infiltrated by recruited monocyte‐derived macrophage precursor cells that engraft into the airway space by transepithelial migration and differentiate into AM (Figure ) …”

“…These cells can be readily isolated from animals and humans from bronchoalveolar lavage and induced sputum and in na€ ıve mice are easily discriminated from other luminal immune cells by their specific phenotypic features. 1 AM include those macrophages located on the luminal surface of the alveolar space which may be obtained by lavage and also those associated with the epithelium of the conducting airways which are the predominant macrophage population sampled in sputum. 2 There are no current methods to distinguish AM from these distinct anatomical sites within the airways.…”

“…2 However, following injury or infection, the resident macrophage pool is rapidly infiltrated by recruited monocyte-derived macrophage precursor cells that engraft into the airway space by transepithelial migration and differentiate into AM (Figure 1). 1 Both airway and interstitial macrophages express the macrophage-specific markers, CD64 and Mertk, in contrast to conventional dendritic cells and monocytes. Additionally, AM are defined phenotypically as autofluorescent SiglecF + CD11c + CD11b À CCR2 À CX3CR1 À cells, whereas interstitial macrophages are non-autofluorescent SiglecF À CD11c +/À CD11b + CCR2 +/À CX3CR1 + cells.…”

Consensus transcriptional states describe human mononuclear phagocyte diversity in the lung across health and disease

“…Local macrophage populations can be replenished by blood monocytes in mice, which can progressively differentiate and acquire macrophage lineage and lung transcriptional markers (Liu et al, 2019;Misharin et al, 2017). The remodeling of the lung myeloid compartment as a whole is a recurring theme across lung diseases based on conventional markers (Baharom et al, 2017). Most recently, large shifts in MNP populations have been described in COVID-19 (Liao et al, 2020).…”

Human Blood and Tonsil Plasmacytoid Dendritic Cells Display Similar Gene Expression Profiles but Exhibit Differential Type I IFN Responses to Influenza A Virus Infection

“…DCs are innate immune cells and professional APCs with the unique capacity to activate naive T cells and thereby initiate pathogen-specific adaptive immune responses, which are typically required to control and clear viral infections. The human immune system has two major groups of DCs, CD11c + myeloid DCs (MDCs) and CD123 + plasmacytoid DCs (PDCs), that have distinct characteristics with several overlapping functions (10)(11)(12). Overall, MDCs, which can be further subdivided into CD141 + MDCs (also known as cDC1) and CD1c + MDCs (also known as cDC2), are the more prevalent DCs and are found in blood and throughout the body lining the skin and mucosal surfaces (13).…”