Identification of Siglec-1-negative alveolar macrophages with proinflammatory phenotypes in chronic obstructive pulmonary disease

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 326; no. 6; pp. L672 - L686
• Main Authors: Saito, Takuya, Fujino, Naoya, Kyogoku, Yorihiko, Yamada, Mitsuhiro, Okutomo, Koji, Ono, Yoshinao, Konno, Shuichi, Endo, Takuto, Itakura, Koji, Matsumoto, Shuichiro, Sano, Hirohito, Aizawa, Hiroyuki, Numakura, Tadahisa, Onodera, Katsuhiro, Okada, Yoshinori, Hussell, Tracy, Ichinose, Masakazu, Sugiura, Hisatoshi
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.06.2024
• Subjects: Aged; Alveoli; Chronic obstructive pulmonary disease; Clinical outcomes; Cytokines - metabolism; Emphysema; Female; Flow cytometry; Gene sequencing; Gene set enrichment analysis; Humans; Inflammation; Inflammation - metabolism; Inflammation - pathology; Lung diseases; Lungs; Macrophages; Macrophages, Alveolar - immunology; Macrophages, Alveolar - metabolism; Macrophages, Alveolar - pathology; Male; Middle Aged; Monocytes; Phenotype; Phenotypes; Pulmonary Disease, Chronic Obstructive - immunology; Pulmonary Disease, Chronic Obstructive - metabolism; Pulmonary Disease, Chronic Obstructive - pathology; Respiratory function; Ribonucleic acid; RNA; Sialic Acid Binding Ig-like Lectin 1 - metabolism; Sputum; Subpopulations; Tumor necrosis factor-α; Siglec-1; alveolar macrophages; COPD; exacerbation
• ISSN: 1040-0605; 1522-1504; 1522-1504
• DOI: 10.1152/ajplung.00303.2023

Alveolar macrophages (AMs) in patients with chronic obstructive pulmonary disease (COPD) orchestrate persistent inflammation in the airway. However, subpopulations of AMs participating in chronic inflammation have been poorly characterized. We previously reported that Siglec-1 expression on AMs, which is important for bacteria engulfment, was decreased in COPD. Here, we show that Siglec-1-negative AMs isolated from COPD lung tissues exhibit a proinflammatory phenotype and are associated with poor clinical outcomes in patients with COPD. Using flow cytometry, we segregated three subsets of AMs based on the expression of Siglec-1 and their side scattergram (SSC) and forward scattergram (FSC) properties: Siglec-1 SSC FSC , Siglec-1 SSC FSC , and Siglec-1 SSC FSC subsets. The Siglec-1 SSC FSC subset number was increased in COPD. RNA sequencing revealed upregulation of multiple proinflammatory signaling pathways and emphysema-associated matrix metalloproteases in the Siglec-1 SSC FSC subset. Gene set enrichment analysis indicated that the Siglec-1 SSC FSC subset adopted intermediate phenotypes between monocytes and mature alveolar macrophages. Functionally, these cells produced TNF-α, IL-6, and IL-8 at baseline, and these cytokines were significantly increased in response to viral RNA. The increase in Siglec-1-negative AMs in induced sputum is associated with future exacerbation risk and lung function decline in patients with COPD. Collectively, the novel Siglec-1 SSC FSC subset of AMs displays proinflammatory properties, and their emergence in COPD airways may be associated with poor clinical outcomes. Alveolar macrophages (AMs) in patients with chronic obstructive pulmonary disease (COPD) orchestrate persistent inflammation in the airway. We find that Siglec-1-negative alveolar macrophages have a wide range of proinflammatory landscapes and a protease-expressing phenotype. Moreover, this subset is associated with the pathogenesis of COPD and responds to viral stimuli.