Human alveolar macrophages display marked hypo-responsiveness to IFN-γ in both proteomic and gene expression analysis

• Published in: PloS one Vol. 19; no. 2; p. e0295312
• Main Authors: Thiel, Bonnie A, Lundberg, Kathleen C, Schlatzer, Daniela, Jarvela, Jessica, Li, Qing, Shaw, Rachel, Reba, Scott M, Fletcher, Shane, Beckloff, Sara E, Chance, Mark R, Boom, W Henry, Silver, Richard F, Bebek, Gurkan
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.02.2024; Public Library of Science (PLoS)
• Subjects: Biology and Life Sciences; Medicine and Health Sciences
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0295312

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 consistent with the aim to limit alveolar inflammation and maintain effective gas exchange in the face of 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 AM remains mostly unknown. In this study, we measured IFN-γ induced protein abundance changes in human AM and autologous blood monocytes (MN). AM cells were activated by IFN-γ stimulation resulting in STAT1 phosphorylation and production of MIG/CXCL9 chemokine. However, the global proteomic response to IFN-γ in AM was dramatically limited in comparison to 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.