Lung Microenvironment and Aging

By 2050, the number of elderly individuals is expected to double to 2 billion. As aging occurs, molecular and physiological changes in the lungs lead to a decline in lung function and weakened immune responses. Stress response pathways are relied upon by lung-resident cells to maintain balance and prevent damage, but these mechanisms become overwhelmed as individuals age, increasing oxidative environments and irreversible damage. Modulating the inflammatory and metabolic pathways in the body, macrophages play a crucial role, particularly alveolar macrophages (AMs), which regulate responses to maintain healthy lung function and encounter airborne pathogens and particulates. Previous research has identified an increased subpopulation of AMs in old mice with a unique inflammatory signature, which may increase the risk of tuberculosis susceptibility in old age (Lafuse et al. J Immunol, 2019). Our current research aims to understand the unique signature of the inflammatory monocyte/macrophage in the setting of old age and the lung alveolar microenvironment using genetically modified murine models (esp. B6.SJL-Ptprca Pepcb/BoyJ (B6.CD45.1), Ms4a3Cre-RosaTdT mice) (Pahari et al. 2023, unpublished). Additionally, our research aims to determine how alterations in AM biology during aging impact the increased risk of airborne infections in the elderly. A comparative study of human, non-human primate and rodent models will provide mechanistic insight into the cellular and molecular processes involved in the origin, recruitment, and differentiation of AMs in old age. It is critical to further our understanding of aging by comprehending the susceptibility of the elderly to various diseases.

Selected Publications

  • Lafuse, William P, Murugesan S Rajaram V, Qian Wu, Juan I Moliva, Jordi B Torrelles, Joanne Turner, and Larry S Schlesinger. (2019) 2019. “Identification of an Increased Alveolar Macrophage Subpopulation in Old Mice That Displays Unique Inflammatory Characteristics and Is Permissive to Mycobacterium Tuberculosis Infection.”. Journal of Immunology (Baltimore, Md. : 1950) 203 (8): 2252-64. https://doi.org/10.4049/jimmunol.1900495.
    Publisher's Version

    The elderly population is more susceptible to pulmonary infections, including tuberculosis. In this article, we characterize the impact of aging on the phenotype of mouse alveolar macrophages (AMs) and their response to Mycobacterium tuberculosis. Uninfected AMs were isolated from bronchoalveolar lavage of young (3 mo) and old (18 mo) C57BL/6 mice. AMs from old mice expressed higher mRNA levels of CCL2, IFN-β, IL-10, IL-12p40, TNF-α, and MIF than young mice, and old mice contained higher levels of CCL2, IL-1β, IFN-β, and MIF in their alveolar lining fluid. We identified two distinct AM subpopulations, a major CD11c+ CD11b- population and a minor CD11c+ CD11b+ population; the latter was significantly increased in old mice (4-fold). Expression of CD206, TLR2, CD16/CD32, MHC class II, and CD86 was higher in CD11c+ CD11b+ AMs, and these cells expressed monocytic markers Ly6C, CX3CR1, and CD115, suggesting monocytic origin. Sorted CD11c+ CD11b+ AMs from old mice expressed higher mRNA levels of CCL2, IL-1β, and IL-6, whereas CD11c+ CD11b- AMs expressed higher mRNA levels of immune-regulatory cytokines IFN-β and IL-10. CD11c+ CD11b+ AMs phagocytosed significantly more M. tuberculosis, which expressed higher RNA levels of genes required for M. tuberculosis survival. Our studies identify two distinct AM populations in old mice: a resident population and an increased CD11c+ CD11b+ AM subpopulation expressing monocytic markers, a unique inflammatory signature, and enhanced M. tuberculosis phagocytosis and survival when compared with resident CD11c+ CD11b- AMs, which are more immune regulatory in nature.