Upregulation of leukocyte immunoglobulin-like receptor B4 on interstitial macrophages in COPD; their possible protective role against emphysema formation

• Published in: Respiratory research Vol. 22; no. 1; p. 232
• Main Authors: Mitsune, Ayumi, Yamada, Mitsuhiro, Fujino, Naoya, Numakura, Tadahisa, Ichikawa, Tomohiro, Suzuki, Ayumi, Matsumoto, Shuichiro, Mitsuhashi, Yoshiya, Itakura, Koji, Makiguchi, Tomonori, Koarai, Akira, Tamada, Tsutomu, Endo, Shota, Takai, Toshiyuki, Okada, Yoshinori, Suzuki, Satoshi, Ichinose, Masakazu, Sugiura, Hisatoshi
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 23-08-2021; BioMed Central; BMC
• Subjects: Animals; Antibodies; Care and treatment; Cell suspensions; Cells, Cultured; Chronic obstructive pulmonary disease; Computed tomography; Disease; Drug receptors; Elastase; Emphysema; Emphysema, Pulmonary; Flow cytometry; Health aspects; Humans; Immune system; Immunoglobulins; Inflammation; Laboratory animals; Lavage; Lesions; Leukocytes; Lung diseases; Lung diseases, Obstructive; Lungs; Macrophages; Macrophages, Alveolar - immunology; Macrophages, Alveolar - metabolism; Macrophages, Alveolar - pathology; Matrix metalloproteinase 12; Membrane Glycoproteins - biosynthesis; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Negative feedback; Obstructive lung disease; Pathogenesis; Patients; Prevention; Pulmonary Disease, Chronic Obstructive - immunology; Pulmonary Disease, Chronic Obstructive - metabolism; Pulmonary Disease, Chronic Obstructive - pathology; Pulmonary emphysema; Pulmonary Emphysema - immunology; Pulmonary Emphysema - metabolism; Pulmonary Emphysema - pathology; Pulmonary macrophage; Receptors; Receptors, Immunologic - biosynthesis; Respiratory diseases; Respiratory function; Risk factors; Smoking; Software; Steroids; Up-Regulation - physiology; Japan; United States > US; Matrix metalloproteinase 12; Pulmonary macrophage; Pulmonary emphysema
• ISSN: 1465-993X; 1465-9921; 1465-993X; 1465-9921
• DOI: 10.1186/s12931-021-01828-3

Leukocyte immunoglobulin-like receptor B4 (LILRB4) is one of the inhibitory receptors in various types of immune cells including macrophages. Previous reports suggested that LILRB4 could be involved in a negative feedback system to prevent excessive inflammatory responses. However, its role has been unclear in chronic obstructive pulmonary disease (COPD), in which macrophages play a crucial role in the pathogenesis. In this study, we aimed to examine the changes of LILRB4 on macrophages both in the lung specimens of COPD patients and the lungs of a mouse emphysema model. We then tried to compare the differences in both inflammation and emphysematous changes of the model between wild-type and LILRB4-deficient mice in order to elucidate the role of LILRB4 in the pathogenesis of COPD.
We prepared single-cell suspensions of resected lung specimens of never-smokers (n = 21), non-COPD smokers (n = 16), and COPD patients (n = 14). The identification of LILRB4-expressing cells and the level of LILRB4 expression were evaluated by flow cytometry. We analyzed the relationships between the LILRB4 expression and clinical characteristics including respiratory function. In the experiments using an elastase-induced mouse model of emphysema, we also analyzed the LILRB4 expression on lung macrophages. We compared inflammatory cell accumulation and emphysematous changes induced by elastase instillation between wild-type and LILRB4-deficient mice.
The levels of surface expression of LILRB4 are relatively high on monocyte linage cells including macrophages in the human lungs. The percentage of LILRB4
cells in lung interstitial macrophages was increased in COPD patients compared to non-COPD smokers (p = 0.018) and correlated with the severity of emphysematous lesions detected by CT scan (r
 = 0.559, p < 0.001), whereas the amount of smoking showed no correlation with LILRB4 expression. Increased LILRB4 on interstitial macrophages was also observed in elastase-treated mice (p = 0.008). LILRB4-deficient mice showed severer emphysematous lesions with increased MMP-12 expression in the model.
LILRB4 on interstitial macrophages was upregulated both in human COPD lungs and in a mouse model of emphysema. This upregulated LILRB4 may have a protective effect against emphysema formation, possibly through decreasing MMP-12 expression in the lungs.