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.

Keywords: bronchial tissue; bronchoalveolar lavage; dendritic cells; lung tissue; macrophages; monocytes; pulmonary; respiratory.

Figure 1

The embryonic and hematopoietic development of mononuclear phagocytes (MNPs) in mice and men. (A) In mice, monocytes, dendritic cells (DCs), and macrophages originate from distinct lineages. DCs (left panel) and monocytes (middle panel) originate from hematopoietic stem cell (HSC) precursors known as committed DC progenitor (CDP) and common monocyte progenitor (cMop), respectively. Some tissue macrophages have an embryonic origin, either from yolk sac macrophages or fetal liver monocytes (right panel). DCs express different transcription factors critical to their development, such as basic leucine zipper ATF-like 3 (BATF3) for cDC1s, interferon regulatory factor 4 (IRF4) for cDC2s, and E2-2 for plasmacytoid DCs (PDCs). MNPs are also differentially dependent on various growth factors such as Fms-related tyrosine kinase 3 ligand (FLT3L) for DCs (left panel), CSF1 and CSF2 for monocytes (middle panel), and colony-stimulating factor 1 (CSF1) and CSF2 and IL-34 for macrophages (right panel). (B) In humans, in vitro culture models have been used to recapitulate in vivo DC hematopoiesis employing progenitors from human cord blood and bone marrow; hGMP, human granulocyte–monocyte–DC progenitor; hMDP, human monocyte–DC progenitor; hCDP, human common DC progenitor; hprec-DC, human migratory precursor.

Figure 2

Identities of human mononuclear phagocytes (MNPs) differ in specific respiratory compartments sampled by different methods. Alveolar macrophages (AMs), interstitial macrophages (IM), tissue monocytes, monocyte-derived dendritic cells (mo-DCs), and three subsets of bona fide dendritic cells including cDC1, cDC2, and plasmacytoid DCs (PDCs) have been documented in different compartments of the human respiratory tract. (A) Cells within the lung parenchymal tissue can be assessed in whole lungs or surgical resections. Cellular components of the airways can be sampled by performing lavages including (B) a shallow bronchial wash or (C) a deeper bronchoalveolar lavage, whereas (D) cells within the respiratory mucosal tissue can be sampled by taking mucosal biopsies. Lung illustration modified from Servier Medical Art.