Cigarette smoke prevents M1 polarization of alveolar macrophages by suppressing NLRP3

Chronic obstructive pulmonary disease (COPD) is an inflammatory condition mainly caused by cigarette smoke (CS). Alveolar macrophages (AMs) contribute to its development, although the polarization of AMs is controversial. This study explored the polarization of AMs and mechanisms underlying their involvement in COPD. AM gene expression data from non-smokers, smokers, and COPD patients were downloaded from the GSE13896 and GSE130928 datasets. Macrophage polarization was evaluated by CIBERSORT and gene set enrichment analysis (GSEA). Polarization-related differentially expressed genes (DEGs) were identified in GSE46903. KEGG enrichment analysis and single sample GSEA were performed. M1 polarization levels were decreased in smokers and COPD patients, whereas M2 polarization did not change. In the GSE13896 and GSE130928 datasets, 27 and 19 M1-related DEGs, respectively, showed expression changes opposite to those in M1 macrophages in smokers and COPD patients compared with the control group. These M1-related DEGs were enriched in NOD-like receptor signaling pathway. Next, C57BL/6 mice were divided into control, lipopolysaccharide (LPS), CS, and LPS + CS groups, and cytokine levels in bronchoalveolar lavage fluid (BALF) and AM polarization were determined. The expression of macrophage polarization markers and NLRP3 was determined in AMs treated with CS extract (CSE), LPS, and an NLRP3 inhibitor. Cytokines levels and the percentage of M1 AMs in BALF were lower in the LPS + CS group than in the LPS group. Exposure to CSE downregulated the expression of M1 polarization markers and NLRP3 induced by LPS in AMs. The present results indicate that M1 polarization of AMs is repressed in smokers and COPD patients, and CS may inhibit LPS-induced M1 polarization of AMs by suppressing NLRP3.