Particulate matter 2.5 promotes pulmonary fibrosis in allergic asthma through macrophage reprogramming toward the M2 phenotype

Inhaled particulate matter 2.5 (PM2.5, ≤ 2.5 μm) exacerbates airway inflammation and promotes fibrosis in allergic asthma. However, most studies have focused on airway inflammation, and direct evidence linking PM2.5 to fibrosis in allergic asthma remains limited. Here, we investigated how PM2.5 promotes fibrotic progress in allergic asthma, focusing on macrophage plasticity. PM2.5 induced neutrophil-dominant acute inflammation, whereas house dust mite (HDM) induced T helper 2- and immunoglobulin (Ig) E-dependent allergic responses accompanied by airway hyperresponsiveness. Strikingly, combined exposure to HDM and PM2.5 progressed beyond airway inflammation to pulmonary fibrosis, with upregulated tumor necrosis factor (TNF)-α, interleukin (IL)-5, IL-13, IgE, collagen I, and transforming growth factor-β 1 and accumulated PM2.5-laden macrophages in the lung. Transcriptomic analysis revealed that combined exposure disrupted the M1/M2 balance, shifting toward M2 dominance. Flow cytometry and western blotting further showed that HDM-induced M1 + and M1 + M2 + populations were reprogrammed toward an M2-biased phenotype, with predominance of M2c-associated IL-10 expression. Furthermore, increased TNF-α and IL-13 in the combined exposure were consistent with the M2a and M2b phenotypes. Collectively, these results demonstrate that PM2.5 promotes pulmonary fibrosis beyond airway inflammation through macrophage reprogramming into a mixed M2a/M2b/M2c profile, highlighting macrophage plasticity as a key mechanism in allergic asthma.