The cell with many faces: lung macrophage plasticity and function in response to environmental and pathogenic insults

Alveolar macrophages (AMs) are pivotal immune sentinels, essential for maintaining tissue homeostasis and mediating immune responses to inhaled particles and pathogens. They demonstrate remarkable plasticity by transitioning from proinflammatory (M1) and anti-inflammatory/reparative (M2) phenotypes in response to local signals. Upon exposure to environmental agents, such as particulate matter, atypical respiratory pathogens, opportunistic Gram-negative bacteria, or respiratory viruses, they undergo dynamic activation that profoundly influences their functional repertoire. Acute or chronic environmental/biological insults disrupt normal AM activities such as phagocytosis, efferocytosis, and cytokine production, inciting oxidative stress, inflammasome activation, and in some cases forms of programmed cell death such as pyroptosis. Although these responses are indispensable for eliminating noxious particles and pathogens, such as Mycoplasma pneumoniae or Klebsiella pneumoniae, influenza A, or SARS-CoV-2, they can also derail the resolution phase by perpetuating inflammation, driving tissue remodeling and fibrosis, and thereby fueling chronic lung disorders such as chronic obstructive pulmonary disease (COPD), pneumoconiosis, and post-COVID interstitial lung disease. Moreover, environmental and microbial exposures modify AMs by altering receptor repertoires, intracellular phenotype by signaling cascades, and cross talk with epithelial and mesenchymal cells that collectively determine the disease trajectory. Elucidating how diverse environmental agents, together with pathogens such as M. pneumoniae, K. pneumoniae, influenza A, and SARS-CoV-2, shape AM biology is therefore pivotal for understanding the pathogenesis of COPD, pneumoconiosis, progressive fibrotic lung disease, and COVID-19-related pulmonary sequelae. This review brings together the current insights into exposure-driven modulation of AM functions, highlighting recent advances and identifying knowledge gaps relevant for therapeutic targeting of exposure-induced and pathogen-mediated lung pathology.