Chronic obstructive pulmonary disease (COPD) is a devastating lung disease with high morbidity, mortality, as well as personal and societal burdens worldwide [1]. Exposure to inhaled noxious particles, including tobacco smoke and pollutants, is the major risk factor for COPD. Fine particulate matter (PM2.5), which has a diameter of < 2.5 μm, increases the risks for cardiovascular disease, stroke and respiratory disease [2], [3]. Recent epidemiological studies, however, reveal that PM2.5 exposure is not significantly associated with the risk of death from respiratory disease, including COPD, for unknown reasons [4]. They demonstrated that PM2.5 at low concentrations increases the risk of death from respiratory diseases, while high concentrations of PM2.5 unexpectedly reduce the risk of death [4]. Therefore, it is necessary to deeply explore the complicated and paradoxical roles of PM2.5 in respiratory diseases.

Trained memory, also known as trained immunity, is an evolutionary perspective in immunology in which innate immune cells have the characteristics of immune memory [5]. Trained immunity occurs mainly on intrinsic immune cells such as macrophages, monocytes, and dendritic cells. Alveolar macrophages are sentinel cells in the airways that clear PM2.5 and pathogens [6]. Respiratory adenoviral infection induces lasting innate memory alveolar macrophages (AMs) and promotes neutrophil infiltration, which results in excessive trained immunity [7], [8]. However, a reduction in phagocytosis by murine AMs and susceptibility to secondary pneumonia followed recovery from primary infection, which exhibits inhibitory trained immunity [7], [9]. The molecular mechanisms of trained immunity are partly known, with glycolytic metabolism and epigenetic-based rewiring being considered to play a central role. The stimuli for trained immunity are mainly pathogen components and/or vaccines. Whether the air pollutant PM2.5 may potentially activate intrinsic immune cells to induce trained immunity, causing physiological and pathological changes, remains largely unknown.

PM2.5 is complex in composition, containing inorganic substances, metal particles, and organic soluble components [10]. High-performance liquid chromatography (HPLC) analysis showed that the PM2.5 used in our experimental collection contained a variety of polycyclic aromatic hydrocarbons (PAHs) [11]. The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, is a distinctive cellular “chemical sensor” ubiquitously expressed in multiple cell types, including macrophages, mast cells, dendritic cells, epithelial cells and T cells [12], [13], [14], [15], [16]. Recent discoveries highlight the potential roles of the AhR-PAH axis in inflammatory and allergic diseases [17]. PAHs bind to AhR, and nuclear translocation localization occurs via the aromatic hydrocarbon receptor nuclear translocator (ARNT) protein [18]. Although PAHs promote macrophage activation [19], PAHs reduce the ability of macrophages to kill Mycobacterium tuberculosis [20]. PM2.5 triggers lung cancer metastasis via AhR signaling [11]. Additionally, PM-associated PAHs have been suggested to aggravate asthma in mice [15], [17]. IL-33 is an epithelial-derived IL-1β family cytokine. It has been reported that atmospheric pollutant diesel exhaust particles promote IL-33 secretion from airway epithelial cells via the AhR/ARNT pathway [21]. Following activation with IL-33, the glycolytic rate is elevated in macrophages [22], [23], [24], [25], thus affecting various physiological functions.

The aim of the present study was to determine the long-term and late effects of PM2.5 in COPD and to explore whether trained immunity was involved. We hypothesized that PAHs in the air pollutant PM2.5 stimulated the AHR/ARNT signaling pathway in alveolar epithelial cells, which promoted IL-33 secretion and the induction of trained immunity in AMsin COPD.