Efferocytosis Mediated By Tam Receptors Maintains Lung Homeostasis And Controls Inflammation In A Mouse Model Of Silicosis

Abstract Alveolar macrophages (AMs) are key cells for the establishment of pulmonary homeostasis. Efferocytosis is one of the main regulatory mechanisms for maintaining tolerance and homeostasis. The TAM receptor family (Tyro3, Axl and MerTk) mediates efferocytosis and inhibits proinflammatory pathways through Gas6 or Protein S binding to phosphatidylserine on apoptotic cells. Here we investigated how lung macrophages are regulated by TAM receptors in homeostasis and during silicosis. We found that LPS-stimulated AMs have an impaired ability to secrete IL-1b, IL-6, IFN-b, and MCP-1, but produce high levels of TNF-a and lower levels of IL-10, compared to bone marrow derived macrophages (BMDM). During homeostasis, AMs from wild type (WT) mice showed high expression of Axl, MerTk, and Gas6 by RT-PCR. Compared to WT mice, Axl−/− and MerTk−/− mice had more airway cells, less TGF-b and IL-10, and higher levels of IL-17 and KC within BAL. In addition, both KO mice had a higher frequency and number of AMs in the BAL, and secreted high levels of MCP-1, IFN-b, GM-CSF, and IL-10 following LPS stimulation compared to WT mice. Fifteen days after intra-tracheal silica instillation (SiO2; 20 mg), Axl−/− and MerTk−/− mice lost more body weight, and had increased lung weight, and percentage and number of neutrophils in the BAL compared to WT mice. Furthermore, both KO mice had a decreased percentage of AMs, and higher levels of KC, TNF-α and TGF-β but lower levels of IL-10 in the BAL compared to WT mice. Finally, Axl−/− mice had higher levels of IL-1β and IL-6 in the BAL than MerTk−/− mice. Our data suggest that efferocytosis mediated by Axl and MerTk receptors plays an important role in maintaining homeostasis and controlling inflammation in the pulmonary mucosae.