STAT6 induces expression of Gas6 in macrophages to clear apoptotic neutrophils and resolve inflammation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 33; pp. 16513 - 16518
• Main Authors: Nepal, Saroj, Tiruppathi, Chinnaswamy, Tsukasaki, Yoshikazu, Farahany, Joseph, Mittal, Manish, Rehman, Jalees, Prockop, Darwin J., Malik, Asrar B.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 13.08.2019
• Subjects: Adoptive Transfer; Animal models; Animals; Apoptosis; Biological Sciences; Bone marrow; Bronchus; Cell activation; Cell Adhesion Molecules - metabolism; Cytokines; Female; Homeostasis; Inflammation; Inflammation - metabolism; Inflammation - pathology; Injuries; Intercellular Signaling Peptides and Proteins - metabolism; Interleukin 4; Interleukin-4 - metabolism; Leukocytes (neutrophilic); Ligands; Lipopolysaccharides; Lung Injury - pathology; Lungs; Macrophages; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Neutrophils; Neutrophils - metabolism; Phagocytosis; Phenotype; Phenotypes; Priming; Pulmonary Alveoli - metabolism; Pulmonary Alveoli - pathology; Stat6 protein; STAT6 Transcription Factor - metabolism; Transcription activation; Gas6; macrophage; STAT6
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1821601116

Efferocytosis of apoptotic neutrophils (PMNs) by alveolar macrophages (AMΦs) is vital for resolution of inflammation and tissue injury. Here, we investigated the role of AMΦ polarization and expression of the efferocytic ligand Gas6 in restoring homeostasis. In the murine model of lipopolysaccharide (LPS)-induced acute lung injury (ALI), we observed augmented temporal generation of cytokines IL-4 and TSG6 in bronchoalveolar fluid (BALF). Interestingly, we also observed increased expression of antiinflammatory markers consistent with a phenotype shift in AMΦs. In particular, AMΦs expressed the efferocytic ligand Gas6. In vitro priming of bone marrow–derived macrophages (BMMΦs) with IL-4 or TSG6 also induced MΦ transition and expression of Gas6. TSG6- or IL-4–primed BMMΦs induced efferocytosis of apoptotic PMNs compared with control BMMΦs. Adoptive transfer of TSG6- or IL-4–primed BMMΦs i.t. into LPS-challenged mice more rapidly and effectively cleared PMNs in lungs compared with control BMMΦs. We demonstrated that expression of Gas6 during AMΦ transition was due to activation of the transcription factor signal transducer and activator of transcription-6 (STAT6) downstream of IL-4 or TSG6 signaling. Adoptive transfer of Gas6-depleted BMMΦs failed to clear PMNs in lungs following LPS challenge and mice showed severely defective resolution of lung injury. Thus, activation of STAT6-mediated Gas6 expression during macrophage phenotype transition resulting in efferocytosis of PMNs plays a crucial role in the resolution of inflammatory lung injury.