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Published on: October 22, 2019
CXCL4 deficiency limits M4 macrophage infiltration and attenuates hyperoxia-induced lung injury
Bingrui Yu1, Siyuan Jia1, Yu Chen1
1Department of Neonatology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, No.1 Western Huanghe Road, Huai'an, Jiangsu, 223300, China.
Background:
Bronchopulmonary dysplasia (BPD), a chronic lung disease prevalent among premature infants, significantly impacts lifelong respiratory health. Macrophages, as key components of the innate immune system, play a role in lung tissue inflammation and injury, exhibiting diverse and dynamic functionalities. The M4 macrophage, a distinctive subtype primarily triggered by chemokine (C-X-C motif) ligand 4 (CXCL4), has been implicated in pulmonary inflammatory and fibrotic processes. Nonetheless, its contribution to the pathophysiology of BPD remains uncertain.
Objective:
This study aimed to elucidate the involvement of CXCL4 in hyperoxia-induced neonatal lung injury and fibrosis, with a particular focus on its influence on M4 macrophages.
Methods:
A BPD model in neonatal mice was established through continuous exposure to 95% O2 for 7 days. Comparative analyses of lung damage and subsequent regeneration were conducted between wild-type (WT) and CXCL4 knockout (KO) mice. Lung tissue inflammation and fibrosis were assessed using histological and immunofluorescence staining, enzyme-linked immunosorbent assay, Western blot, and real-time quantitative polymerase chain reaction. Differentiation of M0 and M4 macrophages was performed in vitro using macrophage colony-stimulating factor and CXCL4, while expressions of S100A8 and MMP7, along with migration assays, were evaluated.
Results:
Elevated CXCL4 levels and M4 macrophage activation were identified in the lung tissue of BPD model mice. CXCL4 deficiency conferred protection to alveolar type 2 epithelial cells, reduced sphingosine-1-phosphate metabolic activity, mitigated pulmonary fibrosis, and limited M4 macrophage progression. This deletion further enhanced lung matrix remodeling during recovery. In vitro, CXCL4 promoted M4 macrophage differentiation and increased macrophage migration via chemokine (C-C motif) receptor 1.
Conclusion:
CXCL4 contributes to hyperoxia-induced lung injury and fibrosis through modulation of cytokine release, alveolar cell proliferation, lipid metabolism, and the regulation of macrophage phenotype and function.
Insights
Chemokine (C-X-C motif) ligand 4 (CXCL4) exacerbates lung injury and fibrosis in bronchopulmonary dysplasia (BPD) by activating M4 macrophages. Reducing CXCL4 protects against hyperoxia-induced lung damage and promotes repair in neonatal mice.
Area of Science:
- Pulmonary Medicine
- Immunology
- Neonatology
Background:
- Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature infants.
- Macrophages, particularly the M4 subtype induced by CXCL4, are implicated in lung inflammation and fibrosis.
- The role of CXCL4 and M4 macrophages in BPD pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the role of CXCL4 in hyperoxia-induced neonatal lung injury and fibrosis.
- To determine the influence of CXCL4 on M4 macrophage activation and function in BPD.
Main Methods:
- A mouse model of BPD was created using hyperoxia exposure.
- Lung injury, inflammation, and fibrosis were assessed in wild-type and CXCL4 knockout mice.
- In vitro studies examined M4 macrophage differentiation and migration promoted by CXCL4.
Main Results:
- CXCL4 and M4 macrophage activation were increased in BPD model mice.
- CXCL4 deficiency protected against lung injury, reduced fibrosis, and enhanced lung repair.
- CXCL4 promoted M4 macrophage differentiation and migration in vitro.
Conclusions:
- CXCL4 contributes to hyperoxia-induced lung injury and fibrosis in BPD.
- CXCL4 modulates cytokine release, cell proliferation, lipid metabolism, and macrophage phenotype.
- Targeting CXCL4 may offer a therapeutic strategy for BPD.
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