Respiratory exposure to 6PPD-quinone aggravates Klebsiella pneumoniae pneumonia by impairing the innate immune function of alveolar macrophages.

N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPD-Q) has garnered considerable attention due to its deadly biological toxicity. However, the effects of 6PPD-Q exposure on mammalian respiratory function remain uncertain. This study developed a murine model using 14-day consecutive intranasal administration of environmentally relevant 6PPD-Q doses, followed by intratracheal Klebsiella pneumoniae (KP) injection, to evaluate the biological effects of 6PPD-Q respiratory exposure on pulmonary innate immunity. Our findings revealed that 6PPD-Q respiratory exposure induced significant damage to lung but not to extrapulmonary organs. Notably, mice respiratorily exposed to 6PPD-Q exhibited with more severe intrapulmonary inflammation, higher bacterial load, and poorer survival rates when challenged with KP pneumonia. These phenomena may be attributed to the increase in CD11c+CD11b+ alveolar macrophages (AMs) in the lungs, which exhibit impaired innate immune functions and attenuated chemotactic responsiveness. Transcriptome analysis further demonstrated downregulated expression of chemokine genes Ccl2, Cxcl1, and Cxcl2 in CD11c+CD11b+ AMs. Overall, our findings reveal that 6PPD-Q respiratory exposure aggravates bacterial pneumonia by impairing the innate immune functions of AMs. These findings enhance our understanding of 6PPD-Q health risks and provide a scientific foundation for developing effective treatments for 6PPD-Q-induced respiratory disorders.