Diesel Soot Paralyzes the Lung’s Resident Scavenger Cells, New Study Finds

Diesel exhaust is one of the most familiar hazards of modern urban life, yet the precise way it undermines the lungs’ defenses has remained surprisingly murky. A new study published in Advanced Biotechnology now offers a strikingly detailed answer, showing that diesel particulate matter disables the lung’s most important resident immune cells by breaking down the very cellular machinery they need to move and to swallow debris. The consequence, the researchers report, is a dangerous buildup of pulmonary surfactant that mirrors a rare but serious lung disease.

The team, led by researchers at Sun Yat-sen University in Guangzhou, China, focused on tissue-resident alveolar macrophages, or TR-AMs, the long-lived sentinels that populate the alveoli, the tiny air sacs where oxygen exchange takes place. These cells originate from fetal liver monocytes and sustain themselves largely without replacement from the bloodstream, outnumbering interstitial macrophages in the lung by roughly eight to one. Under healthy conditions, they patrol nearly continuously between alveoli, engulfing inhaled bacteria, particles, and dying cells, while also clearing and catabolizing excess pulmonary surfactant, the lipid-protein film that keeps the air sacs from collapsing. Nearly ninety percent of them actively migrate as part of routine immune surveillance, making them both the lung’s first responders and its housekeeping crew.

Previous work on particulate pollution and macrophages had largely relied on monocyte-derived cell lines such as THP-1 and U937, which model recruited immune cells rather than the resident alveolar lineage. The new study set out to close that gap by examining how diesel particulate matter, or DPM, affects the two physiological functions that define TR-AM biology: chemotactic movement and phagocytosis. DPM is a major contributor to fine particulate pollution in urban and industrialized environments, and roughly half to ninety percent of it consists of ultrafine particles smaller than 0.1 micrometers, small enough to penetrate deep into the alveolar spaces where these macrophages live.

The researchers began with the murine alveolar macrophage cell line MH-S, exposing cells to a standardized DPM preparation for 24 hours and then performing RNA sequencing. The exposure produced sweeping transcriptional changes, with 287 genes upregulated and 219 downregulated. Pathway analysis revealed disruption in phagosome and actin cytoskeleton regulation, bacterial recognition, and cytokine signaling. Genes encoding integrins and complement receptors essential for adhesion, migration, and bacterial uptake, including Itgal, Itgam, Fpr1, Fpr2, C5ar1, C1qa, and C1qc, were significantly suppressed, and flow cytometry confirmed reduced surface expression of the CD11a and CD11b integrin proteins.

Functional testing followed. In transwell migration assays, DPM-treated macrophages showed a dramatic loss of their ability to migrate toward chemoattractants produced at sites of bacterial stimulation. Notably, the cells’ secretion of chemokines, the signals used to recruit other immune cells, was largely unchanged, suggesting that diesel particles primarily cripple the macrophages’ own motility and receptor signaling rather than their communication role. Phagocytosis assays using fluorescently labeled Escherichia coli and Staphylococcus aureus bioparticles showed sharply reduced uptake and impaired phagosome acidification in DPM-exposed cells, indicating that both particle engulfment and the maturation of the digestive compartment were compromised.

To confirm these findings in living animals, the team exposed mice to DPM via intratracheal instillation and then delivered fluorescent bacterial bioparticles directly into the airways. Primary TR-AMs, identified by their characteristic CD45-high SiglecF-positive surface profile, showed a marked reduction in the ability to phagocytose both bacterial species, and the proportion of highly phagocytic cells fell substantially. The deficit proved durable: phagocytic capacity remained suppressed for weeks after exposure, with only a gradual recovery trend over an eight-week observation period. Conditioned-medium experiments showed that the effect was driven mainly by direct contact between particles and macrophages, though epithelial cells exposed to DPM released soluble mediators that added a smaller, indirect layer of inhibition.

The mechanistic core of the study lies in the actin cytoskeleton. Both migration and phagocytosis depend on the polymerization of filamentous actin, or F-actin, which provides the mechanical force for cell deformation, filopodia extension, and the engulfment of particles larger than half a micrometer. DPM exposure significantly reduced phalloidin staining of F-actin in macrophages, and the loss of polymerization tracked closely with a more than tenfold decrease in bacterial uptake. When the researchers treated cells with cytochalasin D, a drug that disrupts filamentous actin, phagocytosis collapsed in the same way, confirming that actin remodeling is indispensable for the process. DPM also reduced the expression of the upstream regulators of actin nucleation, including the GTPases Rac1 and Cdc42, the nucleation-promoting factors WASP, N-WASP, and WAVE, and the Arp2 and Arp3 components of the actin-nucleating complex, pointing to suppression of the Rac1/Cdc42-WASP-Arp2/3 signaling cascade as a likely driver of the functional failure.

The downstream consequences for lung physiology were equally striking. Because TR-AMs are responsible for clearing excess surfactant, their paralysis led to measurable accumulation in the alveoli. Mice exposed to DPM developed Periodic acid-Schiff-positive granules in the alveolar spaces, a histological signature of accumulated surfactant glycoproteins and lipoprotein deposits. Bronchoalveolar lavage fluid showed sharply elevated total protein, a roughly 120-fold increase in surfactant protein D, elevated lactate dehydrogenase indicating cell death, and a slight decline in surfactant protein A, the collectin that normally facilitates lipid clearance. Targeted lipidomics revealed excessive accumulation of phosphatidylcholine species that normally constitute the bulk of surfactant lipids, along with ceramides and free cholesterol. In vitro, DPM-treated macrophages showed significantly reduced uptake of fluorescent cholesterol, linking the cellular defect directly to the lipid buildup observed in the animals.

That pattern, the authors note, closely resembles pulmonary alveolar proteinosis, a disease in which surfactant accumulates, gas exchange fails, and infection risk rises. While primary forms of the disease stem from defects in granulocyte-macrophage colony-stimulating factor signaling, secondary alveolar proteinosis arises from external insults that deplete or disable alveolar macrophages, and inhaled particles including indium and gallium compounds have already been implicated. The new findings suggest that diesel particulate exposure may represent another route to this pathology, offering a mechanistic bridge between everyday air pollution and a condition that is frequently underdiagnosed.

The researchers are careful to acknowledge the limits of their model. The acute murine exposure protocol compresses what would be months of real-world inhalation into concentrated instillations, and although the authors estimate that the cumulative dose corresponds to roughly six days of occupational exposure in a high-concentration underground mining environment, long-term inhalation studies will be needed to confirm relevance to ordinary urban exposure. The evidence linking the Rac1/Cdc42-WASP-Arp2/3 pathway to the observed dysfunction remains correlative, and direct measurement of chemotaxis in primary TR-AMs was not performed. Even so, the study delivers a clear and consequential message: the same soot that darkens city air can quietly disarm the lung’s resident defenders, weakening immune surveillance, delaying inflammation resolution, and allowing surfactant to accumulate where it can do real harm. Restoring macrophage actin dynamics, the authors suggest, may one day offer a therapeutic strategy for pollution-related respiratory disease.

Subject of Research: Impairment of tissue-resident alveolar macrophage phagocytosis by diesel particulate matter and its role in pulmonary surfactant accumulation

Article Title: Phagocytotic impairment of tissue-resident alveolar macrophages by diesel particulates drives pulmonary surfactant accumulation

Article References: Chen, R., Zhou, Z., Wang, J., Zhang, Y., Li, P., & Wu, H. (2026). Phagocytotic impairment of tissue-resident alveolar macrophages by diesel particulates drives pulmonary surfactant accumulation. Advanced Biotechnology, 4(2), Article 21. https://doi.org/10.1007/s44307-026-00113-y

Image Credits: AI Generated

DOI: 10.1007/s44307-026-00113-y

Keywords: diesel particulate matter, alveolar macrophages, phagocytosis, chemotaxis, F-actin, pulmonary surfactant, pulmonary alveolar proteinosis, air pollution, PM2.5, innate immunity, surfactant protein D, lipidomics