The changes and possible roles of KLF4 and monocyte/macrophage subtypes in interstitial lung disease_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

 SUN Liang , LI Xin , JI Wenjie , WEI Luqing

Characteristic Medical Center of the Chinese People's Armed Police Force, Tianjin 300162, P. R. China;

Corresponding?author：

SUN Liang, Email: sunliangys@sina.com

Keywords：

Krüppel-like factor 4; Interstitial pneumonia; Monocyte; Macrophage

DOI：

10.7507/1671-6205.201907018

Video：

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Objective To investigate the role of Krüppel-like factor 4 (KLF4) mediated monocyte/macrophage subtype switch in the pathological progression of pulmonary fibrosis.Methods Thirty-six patients with interstitial pneumonia were recruited from Characteristic Medical Center of the Chinese People's Armed Police Force between May 2015 and January 2017. Peripheral venous blood and bronchoalveolar lavage fluid were collected in the morning. Pulmonary function and arterial blood gas were tested after admission. Flow cytometry was used to test monocyte subtypes of peripheral blood and macrophage subtypes of bronchoalveolar lavage fluid. KLF4 of peripheral blood was detected by enzyme linked immunosorbent assay. Thirty normal subjects were selected as control group of peripheral blood mononuclear cell subtypes and KLF4 (control group A), and 10 patients without pulmonary fibrosis who needed bronchoscopy were selected as control group of macrophage subtypes in alveolar lavage fluid (control group B). The relationship between the expression of KLF4 and the differentiation of monocytes and macrophages were observed. Furthermore, the relationship between the differentiation of monocytes subtypes, macrophages subtypes and lung function were observed.Results Monocyte of CD14⁺⁺CD16^– subtype in pulmonary fibrosis group was significantly lower than that in control group A (P<0.05). Monocyte of CD14⁺⁺CD16⁺ subtype in pulmonary fibrosis group was significantly higher than that in control group A (P<0.05). No significant difference was found between the two groups regarding CD14⁺CD16⁺⁺. No correlation was found between three subtypes of monocyte and D_LCO of patients and between three subtypes of monocyte and PaO₂ of patients. M1 macrophage in pulmonary fibrosis group was significantly lower than that in control group B (P<0.05). M2 macrophage in pulmonary fibrosis group was significantly higher than that in control group B (P<0.05). Negative correlation was found between the ratio of M2 subtypes and D_LCO of patients and between the ratio of M2 subtypes and PaO₂ of patients (P<0.05). KLF4 protein of blood in pulmonary fibrosis group was significantly higher than that in control group A (P<0.05). Positive correlation was found between the ratio of M2 subtypes and KLF4 protein (P<0.05).Conclusions CD16⁺ monocyte plays a role in the occurrence and development of pulmonary fibrosis, but no evidence is found there is a direct correlation between monocyte subtypes of peripheral blood and fibrosis degree of lung tissue. M2 macrophage subtype plays an important role in the development of interstitial pneumonia. The number of M2 macrophages is positively correlated with the severity of pulmonary fibrosis. Monocyte/macrophage subtype differentiation by KLF4 may play a role in the pathological progression of pulmonary fibrosis.

Citation： SUN Liang, LI Xin, JI Wenjie, WEI Luqing. The changes and possible roles of KLF4 and monocyte/macrophage subtypes in interstitial lung disease. Chinese Journal of Respiratory and Critical Care Medicine, 2020, 19(5): 467-473. doi: 10.7507/1671-6205.201907018 Copy

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4.	Belge KU, Dayyani F, Horelt A, et al. The proinflammatory CD14⁺ CD16⁺ DR⁺⁺ monocytes are a major source of TNF. J Immunol, 2002, 168(7): 3536-3542.
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6.	馬永強, 姬文婕, 鄭春秀, 等. 實驗性肺纖維化小鼠循環單核細胞亞群的動態變化及意義. 醫學研究生學報, 2014, 27(9): 909-914.
7.	Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature, 2013, 496(7446): 445-455.
8.	Moghaddam AS, Mohammadian S, Vazini H, et al. Macrophage plasticity, polarization and function in health and disease. J Cell Physiol, 2018, 233: 6425-6440.
9.	Prasse A, Probst C, Bargagli E, et al. Serum CC-chemokine ligand 18 concentration predicts outcome in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2009, 179(8): 717-723.
10.	Tiev KP, Hua-Huy T, Kettaneh A, et al. Serum CC chemokine ligand-18 predicts lung disease worsening in systemic sclerosis. Eur Respir J, 2011, 38(6): 1355-1360.
11.	Bharat A, Bhorade SM, Morales-Nebreda L, et al. Flow cytometry reveals similarities between lung macrophages in humans and mice. Am J Respir Cell Mol Biol, 2016, 54(1): 147-149.
12.	Ji WJ, Ma YQ, Zhou X. Temporal and spatial characterization of mononuclear phagocytes in circulating, lung alveolar and interstitial compartments in a mouse model of bleomycin-induced pulmonary injury. J Immunol Methods, 2014, 403(1-2): 7-16.
13.	Zaynagetdinov R, Sherrill TP, Kendall PL, et al. Identification of myeloid cell subsets in murine lungs using flow cytometry. Am J Respir Cell Mol Biol, 2013, 49(2): 180-189.
14.	Wojtan P, Mierzejewski M, Osińska I, et al. Macrophage polarization in interstitial lung diseases. Cent Eur J Immunol, 2016, 41(2): 159-164.
15.	Yang S, Cui H, Xie N. miR-145 regulates myofibroblast differentiation and lung fibrosis. FASEB J, 2013, 27(6): 2382-2391.
16.	Liu Y, Sinha S, Owens G. A transforming growth factor-beta control element required for SM alpha-actin expression in vivo also partially mediates GKLF-dependent transcriptional repression. J Biol Chem, 2003, 278(48): 48004-48011.
17.	Liao X, Sharma N, Kapadia F, et al. Krüppel-like factor 4 regulates macrophage polarization. J Clin Invest, 2011, 121(7): 2736-2749.

1. 陳雪芬, 姬文婕, 胡道川, 等. Krüppel 樣因子 4 在實驗性肺纖維化小鼠肺組織中的表達及意義. 中國呼吸與危重監護雜志, 2013, 12(5): 509-512.
2. 龐博, 張丹丹, 趙娟, 等. 冠心病患者 CD16⁺ 單核細胞比例與體質量指數之間的相關性研究. 國際檢驗醫學雜志, 2018, 39(24): 3019-3022.
3. Urbanski K, Ludew D, Filip G, et al. CD14⁺ CD16⁺⁺ "nonclassical" monocytes are associated with endothelial dysfunction in patients with coronary artery disease. Thromb Haemost, 2017, 117(5): 971-980.
4. Belge KU, Dayyani F, Horelt A, et al. The proinflammatory CD14⁺ CD16⁺ DR⁺⁺ monocytes are a major source of TNF. J Immunol, 2002, 168(7): 3536-3542.
5. Ziegler-Heitbrock L. The CD14+CD16+blood monocytes: their role in infection and inflammation. J Leukoc Biol, 2007, 81(3): 584-592.
6. 馬永強, 姬文婕, 鄭春秀, 等. 實驗性肺纖維化小鼠循環單核細胞亞群的動態變化及意義. 醫學研究生學報, 2014, 27(9): 909-914.
7. Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature, 2013, 496(7446): 445-455.
8. Moghaddam AS, Mohammadian S, Vazini H, et al. Macrophage plasticity, polarization and function in health and disease. J Cell Physiol, 2018, 233: 6425-6440.
9. Prasse A, Probst C, Bargagli E, et al. Serum CC-chemokine ligand 18 concentration predicts outcome in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2009, 179(8): 717-723.
10. Tiev KP, Hua-Huy T, Kettaneh A, et al. Serum CC chemokine ligand-18 predicts lung disease worsening in systemic sclerosis. Eur Respir J, 2011, 38(6): 1355-1360.
11. Bharat A, Bhorade SM, Morales-Nebreda L, et al. Flow cytometry reveals similarities between lung macrophages in humans and mice. Am J Respir Cell Mol Biol, 2016, 54(1): 147-149.
12. Ji WJ, Ma YQ, Zhou X. Temporal and spatial characterization of mononuclear phagocytes in circulating, lung alveolar and interstitial compartments in a mouse model of bleomycin-induced pulmonary injury. J Immunol Methods, 2014, 403(1-2): 7-16.
13. Zaynagetdinov R, Sherrill TP, Kendall PL, et al. Identification of myeloid cell subsets in murine lungs using flow cytometry. Am J Respir Cell Mol Biol, 2013, 49(2): 180-189.
14. Wojtan P, Mierzejewski M, Osińska I, et al. Macrophage polarization in interstitial lung diseases. Cent Eur J Immunol, 2016, 41(2): 159-164.
15. Yang S, Cui H, Xie N. miR-145 regulates myofibroblast differentiation and lung fibrosis. FASEB J, 2013, 27(6): 2382-2391.
16. Liu Y, Sinha S, Owens G. A transforming growth factor-beta control element required for SM alpha-actin expression in vivo also partially mediates GKLF-dependent transcriptional repression. J Biol Chem, 2003, 278(48): 48004-48011.
17. Liao X, Sharma N, Kapadia F, et al. Krüppel-like factor 4 regulates macrophage polarization. J Clin Invest, 2011, 121(7): 2736-2749.

Chinese Journal of Respiratory and Critical Care Medicine

The changes and possible roles of KLF4 and monocyte/macrophage subtypes in interstitial lung disease

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