Lung surfactant lipids reduce the alternative activation and proliferation of alveolar macrophages induced by IL-4

Abstract

Activation of macrophages by interleukin-4 (IL-4) is needed for tissue repair, although excessive activation causes pathology associated with fibrosis. Alveolar macrophages (AMs) are less able to respond to IL-4 in vivo than macrophages from the peritoneal cavity, due to a still unknown factor of the lung environment. We recently reported that IL-4 is not sufficient for AM alternative activation and that the involvement of surfactant protein A (SP-A) is required. The objective of this study is to investigate whether surfactant lipids, which are continuously endocytosed by alveolar macrophages, could influence IL-4-mediated alternative activation of AMs. Toward that end, isolated AMs were pre-incubated with surfactant lipids to allow their endocytosis and then were stimulated with IL-4 and/or SP-A. Analyses of AM activation, proliferation, and signaling were performed by enzymatic assay, ELISA, and Western blot. Metabolic profiles of AMs were performed by using an extracellular flux analyzer. We found that SP-A+IL-4 increased mitochondrial respiration and glycolysis in AMs, but surfactant phospholipids decreased the acquisition of this metabolic profile. Surfactant lipids also reduce SP-A+IL-4-dependent alternative activation and proliferation of AMs. Mechanistically, endocytosed lipids decreased IL-4+SP-A-dependent activation of the PI3K-Akt-mTORC1 signaling axis, but lipids did not affect IL-4-induced STAT6 phosphorylation. We conclude that alveolar lipids control PI3K-dependent signaling pathways that amplify IL-4 actions in AMs. This suggests that diminution of alveolar lipid levels in some lung diseases may increase IL-4 dependent fibrotic responses.