Ficolin A Derived from Local Macrophages and Neutrophils Protects Against LPS-Induced Acute Lung Injury by Activating Complement

Abstract

Background: Ficolins are important and widely distributed secreted pattern recognition molecules that can induce lectin complement pathway activation and initiate the innate immune response. Although ficolins can bind lipopolysaccharide (LPS) in vitro, the sources, dynamic changes and roles of ficolins in LPS-induced local pulmonary inflammation and injury remain poorly understood. Methods: C57BL/6 and Ficolins-KO mice were intranasally administrated 10 μg LPS to induce acute lung inflammation and injury. Flow cytometry and immunofluorescence were performed to reveal the expression of ficolins. Lung injury was analyzed by hematoxylin & eosin staining. Complement activation was confirmed by immunohistochemistry and sandwich ELISA. Findings: In this study, we found that ficolin A and ficolin B are expressed in leukocytes from the bone marrow, peripheral blood, lung and spleen. Further analyses showed that macrophages and neutrophils are the main sources of ficolin A and ficolin B, and T and B cells also express a small amount of ficolin B. The intranasal administration of LPS induced local pulmonary inflammation with the increased recruitment of macrophages and neutrophils. LPS stimulation induced increased expression of ficolin A and ficolin B in neutrophils at the acute stage, and in macrophages at the late stage. The severity of the lung injury and local inflammation of Fcna−/− mice was increased via the induction of extracellular complement activation. The recovery of LPS-induced local lung inflammation and injury was delayed in Fcnb−/− mice. Interpretation: The local macrophage- and neutrophil-derived ficolin A protects against LPS-induced acute lung injury by mediating extracellular complement activation. These findings suggested that ficolins might be novel therapeutic targets for gram-negative bacteria infection induced pneumonia. Funding Statement: This work was supported by National Science Grant for Distinguished Young Scholars (81425001/H0104), National Natural Science Foundation of China, China (81373114), Beijing Municipal Natural Science Foundation, China (7182013), CAMS Innovation Fund for Medical Sciences, China (CIFMS 2018-I2M-1-003, CIFMS 2016-2M-1-014, 2016-12M-006), the Chinese National Major S & T Project (2017ZX10304402-001). Declaration of Interests: All authors declare no conflicts of interest associated with this manuscript. Ethics Approval Statement: All experiments were conducted with the approval of the Institutional Animal Care and Use Committee (IACUC) of Capital Medical University.