Increasing S1P promotes M1 macrophage in chronic obstructive pulmonary disease and chronic obstructive pulmonary disease-obstructive sleep apnea overlap syndrome via S1PR1/HDAC1 signaling.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow limitation and chronic airway inflammation. Obstructive sleep apnea (OSA) is a common clinical condition with partial or complete pharyngeal collapses occurring repeatedly during sleep. COPD-OSA is the coexistence of COPD and OSA. Abnormal macrophages play important roles in COPD progression. Sphingosine-1-phosphate (S1P) has emerged as an important molecule in COPD. This study aimed to explore the change and potential functional mechanism of S1P in COPD and COPD-OSA. METHODS: Flow cytometry (FCM) was used to detect the M1 and M2 macrophage cell ratio. Enzyme-linked immunosorbent assay (ELISA) was used to detect the S1P levels. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were used to detect the expression levels of S1P receptor 1 (S1PR1) and histone deacetylase 1 (HDAC1). Cytokine levels were detected by multiple microsphere flow immunofluorescence assay. The THP-1 cells of in vitro models were exposed to cigarette smoke extract (CSE). RESULTS: Firstly, we found that the ratio of pro-inflammatory M1 macrophage was increased in COPD and COPD-OSA patients [vs. healthy controls (HCs)], whereas that of anti-inflammatory M2 macrophage was decreased. Notably, compared with COPD alone, COPD-OSA showed more M1 macrophage and less M2 macrophage. Secondly, we observed significantly increased plasma S1P levels in COPD and COPD-OSA (level: COPD-OSA > COPD > HC). Furthermore, the effect of S1P on macrophage polarization was investigated. The results showed that S1P treatment could enhance the efficiency of M1 polarization of THP-1 in response to lipopolysaccharide (LPS)/interferon-γ (IFN-γ) stimulation, which could be reversed by a S1P antagonis-FTY720. Thirdly, we explored the potential mechanism of S1P in macrophage polarization. The data showed that S1P treatment could enhance expression of S1PR1 in THP-1 cells, which could be reversed by FTY720. S1PR1 overexpression could facilitate the M1 polarization of THP-1 in response to LPS/IFN-γ. Correspondingly, in peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages (MDMs) from COPD and COPD-OSA, the S1PR1 expression levels were higher than that from HC. Additionally, HDAC1 expression was decreased in THP-1 by S1P treatment. HDAC1 overexpression could inhibit M1 polarization efficiency of THP-1 in response to LPS/IFN-γ. Notably, the expression of HDAC1 was lower in PBMC and MDM from COPD and COPD-OSA patients (vs. HCs). CONCLUSIONS: This study suggested that increasing S1P levels could facilitate macrophage polarization toward M1 subtype in COPD and COPD-OSA, via enhancing S1PR1 signaling or inhibiting HDAC1 signaling.