Across the globe, millions of people die annually from respiratory disorders including both infectious and inflammatory diseases. Lower tract respiratory infections alone affect over a billion people annually, making this a significant public health concern. The delicate balance between combatting infections and minimizing harm to self-tissue is primarily maintained by the gas-exchanging alveoli in the lower respiratory tract. In this battle, alveolar macrophages (AM) are the first cells to encounter airborne pathogens and environmental particles. The tissue environment heavily influences the phenotype and function of these macrophages, and they differ from other macrophages found in the lung interstitium and other organs. Unfortunately, there are currently no readily available in vitro models of human AMs (HAMs), presenting a major challenge, especially during the COVID-19 pandemic. To advance translational studies and clinical benefits for humans, there is an urgent need for a cost-effective method to generate or expand primary human cells for HAM phenotype. Fortunately, a unique model for producing human alveolar macrophage-like (AML) cells has been developed, involving the differentiation of blood monocytes in vitro using a defined cocktail of lung components that mimic the alveolar environment in cell culture (Pahari et al., mBio 2023). This non-invasive model is significantly less costly than performing a bronchoalveolar lavage to retrieve HAMs and yields more AML cells than HAMs obtained from a single person. The AML model has also been employed to study M. tuberculosis and SARS-CoV-2. Therefore, the AML model is critical to advancing our understanding of respiratory diseases, from COVID-19 and tuberculosis to asthma, cystic fibrosis, and chronic obstructive pulmonary disease.
Selected Publications
Pahari, Susanta, Eusondia Arnett, Jan Simper, Abul Azad, Israel Guerrero-Arguero, Chengjin Ye, Hao Zhang, et al. (2023) 2023. “A New Tractable Method for Generating Human Alveolar Macrophage-Like Cells in Vitro to Study Lung Inflammatory Processes and Diseases”. MBio 14 (4): e0083423. https://doi.org/10.1128/mbio.00834-23.
Alveolar macrophages (AMs) are unique lung resident cells that contact airborne pathogens and environmental particulates. The contribution of human AMs (HAMs) to pulmonary diseases remains poorly understood due to the difficulty in accessing them from human donors and their rapid phenotypic change during in vitro culture. Thus, there remains an unmet need for cost-effective methods for generating and/or differentiating primary cells into a HAM phenotype, particularly important for translational and clinical studies. We developed cell culture conditions that mimic the lung alveolar environment in humans using lung lipids, that is, Infasurf (calfactant, natural bovine surfactant) and lung-associated cytokines (granulocyte macrophage colony-stimulating factor, transforming growth factor-β, and interleukin 10) that facilitate the conversion of blood-obtained monocytes to an AM-like (AML) phenotype and function in tissue culture. Similar to HAM, AML cells are particularly susceptible to both Mycobacterium tuberculosis and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. This study reveals the importance of alveolar space components in the development and maintenance of HAM phenotype and function and provides a readily accessible model to study HAM in infectious and inflammatory disease processes, as well as therapies and vaccines. IMPORTANCE Millions die annually from respiratory disorders. Lower respiratory track gas-exchanging alveoli maintain a precarious balance between fighting invaders and minimizing tissue damage. Key players herein are resident AMs. However, there are no easily accessible in vitro models of HAMs, presenting a huge scientific challenge. Here, we present a novel model for generating AML cells based on differentiating blood monocytes in a defined lung component cocktail. This model is non-invasive, significantly less costly than performing a bronchoalveolar lavage, yields more AML cells than HAMs per donor, and retains their phenotype in culture. We have applied this model to early studies of M. tuberculosis and SARS-CoV-2. This model will significantly advance respiratory biology research.
