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Published on: March 21, 2021
Osteopontin from monocyte-derived dendritic cells mediates ozone-induced pulmonary responses in mice
Hiroki Tashiro1, Yuki Kuwahara1, Yuki Kurihara1
1Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University Hospital, Saga, Japan.
Introduction:
Asthma is a heterogeneous disease characterized by airway inflammation and hyperresponsiveness (AHR). Ozone, a common air pollutant, induces a neutrophilic phenotype of asthma that is resistant to corticosteroids. Osteopontin has been implicated in airway inflammation, but its role in ozone-induced pulmonary responses remains unclear. We hypothesized that osteopontin contributes to neutrophilic airway inflammation and AHR through dendritic cell (DC)-neutrophil interactions.
Methods:
Male BALB/c mice were exposed to ozone (2 ppm, 3 hours) or ambient air. AHR and bronchoalveolar lavage fluid (BALF) cell counts were assessed, and osteopontin levels were measured. Single-cell RNA sequencing of lung tissue was performed to identify osteopontin-producing cells and infer cell-cell communication using CellChat analysis. Functional validation included administration of clodronate liposomes to affect monocyte-derived DCs and an anti-osteopontin neutralizing antibody. In addition, RNA sequencing of bone marrow-derived neutrophils stimulated with osteopontin in vitro was conducted.
Results:
Ozone exposure significantly increased neutrophils in BALF, enhanced AHR, and elevated osteopontin levels in lung tissue. Single-cell RNA sequencing showed DCs, particularly monocyte-derived DCs, as the main source of osteopontin, with downstream signaling to macrophages, fibroblasts, pericytes, smooth muscle cells, and neutrophils. Clodronate liposome treatment reduced osteopontin expression and attenuated ozone-induced neutrophilic inflammation and AHR. Neutralization of osteopontin suppressed neutrophilic airway inflammation but did not significantly improve AHR. In vitro, osteopontin stimulation of neutrophils upregulated NDUFA1, a mitochondrial complex I gene.
Conclusions:
The present findings indicate that ozone exposure induces osteopontin production primarily from monocyte-derived DCs, which promotes neutrophilic airway inflammation through DC-neutrophil interactions, while having a limited impact on airway hyperresponsiveness.
