ACOX1 downregulation contributes to macrophage M1 polarization and neutrophilic airway inflammation in asthma.

BACKGROUND: Acyl-coenzyme A oxidase 1 (ACOX1) is a key enzyme in peroxisomal fatty acid β-oxidation. Fatty acid metabolism is implicated in macrophage polarization which regulates airway inflammation in asthma. METHODS: The expression profiles of the ACOX1-mediated peroxisomal fatty acid β-oxidation pathway were analyzed in the GSE41863 dataset, comparing neutrophilic asthma patients, eosinophilic asthma patients and control subjects. In our cohort of 67 treatment-naive asthma patients and 21 control subjtcts, ACOX1 expression in sputum and bronchoalveolar lavage (BAL) cells were measured. In THP-1 and RAW264.7 cells, M1 markers, M2 markers and lipid accumulation were assessed after ACOX1 knockdown and pharmacological inhibition. Lipid clearance with adipose triglyceride lipase (ATGL) and NF-κB signaling pathway inhibition with BAY 11-7082 were performed. In a mouse model of neutrophil-dominant allergic airway inflammation, the effects of intranasally adeno-associated virus (AAV) vector-mediated Acox1 overexpression and NF-κB signaling activation by diprovocim on macrophage M1 polarization and airway inflammation were evaluated. RNA transcriptome sequencing was performed to explore the underlying mechanism of ACOX1-mediated M1 polarization. RESULTS: ACOX1-mediated peroxisomal fatty acid β-oxidation pathway was significantly downregulated in sputum cells from neutrophilic asthma patients when compared with eosinophilic asthma patients and control subjects. ACOX1 expression was downregulated in sputum cells from non-eosinophilic asthma patients and BAL macrophages from subjects specifically classified as neutrophilic asthma patients. In vitro, ACOX1 overexpression inhibited lipopolysaccharide (LPS)-induced expression of M1 markers including iNOS and IL-1β, whereas ACOX1 knockdown or pharmacological inhibition of ACOX1 promoted M1 polarization without altering M2 markers. Intranasally AAV-mediated Acox1 overexpression in macrophage significantly inhibited the expression of M1 markers and alleviated neutrophilic airway inflammation in the mouse model, while these effects were reversed by diprovocim. Mechanistically, ACOX1 downregulation induces lipid accumulation, which further activates the NF-κB signaling and consequently promotes macrophage M1 polarization. CONCLUSIONS: ACOX1 downregulation contributes to macrophage M1 polarization and neutrophilic airway inflammation through lipid accumulation-upregulated NF-κB signaling in asthma.