Monocyte-derived alveolar macrophage drives inflammatory response to lung ozone exposure

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Abstract: Morbidity and mortality associated with ozone (O3) exposures are a substantial public health concern. Unlike other environmental exposures, O3-related morbidity and mortality, is largely linked to respiratory causes and associated with pre-existing respiratory conditions. However, specific mechanisms underlying this phenomenon are poorly understood. Understanding how prior lung injury drives susceptibility to subsequent O3 exposure is particularly important in the context on viral lung injury, such as pneumonia caused by seasonal influenza virus or SARS-CoV-2, the causative agent of the ongoing COVID-19 pandemic. Our overall hypothesis is that this is driven by distinct alveolar macrophage (AMØ) subsets. During the past decade, work from several groups, including ours, has demonstrated that long-living, self-maintaining, tissue-resident AMØ are the dominant immune cell type in normal mouse and human lung. Tissue-resident AMØ are essential to lung homeostasis and direct responses to pathogens and environmental exposures, including O3. We have previously reported that murine O3 exposure expands tissue-resident AMØ, and their loss exacerbates O3-induced lung injury. Conversely, monocyte-derived AMØ, recruited during lung injury (e.g. viral infection), augment inflammation. Our group previously showed that monocyte-derived AMØ recruited after lung injury persist in the lung via autocrine M-CSF/M-CSF receptor (M-CSF-R), maintain an activated phenotype, and drive chronic lung diseases. Extending this to humans, we demonstrate that the abundance and activation state of monocyte-derived AMØs negatively correlate with pulmonary function in patients with early pulmonary fibrosis. Cumulatively, our published and preliminary data support that distinct AMØ subsets direct the balance between ongoing inflammation and its resolution and suggest that AMØ composition, particularly the baseline presence and activation of monocyte-derived AMØ, prior to exposure can enhance severity and persistence of O3-induced lung injury. This baseline condition is particularly important as respiratory viral infections, including influenza and SARS-CoV2, induce the recruitment of monocyte-derived AMØs. Leveraging mechanistic mouse models, state- of-the-art lineage-tracing systems, single-cell genomics, and serial sampling in controlled human O3 exposures, we will test the hypothesis that the abundance and activation state of monocyte-derived AMØs drive O3- induced lung inflammatory responses via autocrine M-CSF/M-CSF-R signaling. Our specific aims are: Aim 1: To determine the role of autocrine monocyte-derived alveolar macrophage M-CSF/M-CSF-R signaling in maintaining lung inflammation in mouse models of O3-exposure. Aim 2: To determine whether the abundance and activation status of monocyte-derived AMØ predicts lung physiological and inflammatory responses in controlled acute O3 exposures in normal human subjects and in individuals with prior SARS-CoV2 infection. These results would support a novel translational paradigm with important public health implications, and identify a novel therapeutic strategy to revert the adverse public health effects of O3 exposure.