Hypo-responsiveness of human alveolar macrophages to IFN-γ is not due to attenuated STAT1 signaling

Alveolar macrophages (AM) perform a primary defense mechanism in the lung through phagocytosis of inhaled particles and microorganisms. AM are known to be relatively immunosuppressive to limit the inflammatory response and maintain homeostasis under these constant challenges. How AM respond to T cell derived cytokine signals, which are critical to the defense against inhaled pathogens, is less well understood. For example, successful containment of Mycobacterium tuberculosis (Mtb) in lung macrophages is highly dependent on IFN-γ secreted by Th-1 lymphocytes, however, the proteomic IFN-γ response profile in macrophages remains mostly unknown. In this study, we measured IFN-γ induced protein abundance changes in human AM and autologous blood monocytes (MN). The proteome of AM was much less responsive to IFN-γ than that of MN (9 AM vs 89 MN differentially abundant proteins). AM hypo-responsiveness was not explained by reduced JAK-STAT1 signaling nor increased SOCS1 expression. These findings suggest that AM have a tightly regulated response to IFN-γ which may prevent excessive pulmonary inflammation but may also provide a niche for the initial survival and growth of Mtb and other intracellular pathogens in the lung. Significance IFN-γ stimulation of lung macrophages is a key factor in the successful containment and maintenance of asymptomatic latent Mycobacterium tuberculosis and other pulmonary infections in humans. However, the macrophage response at the proteomic level is unknown. In this study we show that the global IFN-γ response in alveolar macrophages is attenuated relative to autologous blood monocytes and this hypo-responsiveness is not due to downregulation of proximal STAT1 signal transduction nor due to upregulation of the SOCS1 inhibitor. These results provide a basis for understanding the global regulation of IFN-γ responsiveness in lung macrophages.