MN peptide abundance measures.

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.

肺泡巨噬细胞（Alveolar macrophages, AM）通过吞噬吸入颗粒物与微生物，执行肺部的核心防御机制。已知AM相对具有免疫抑制特性，这与其在持续面临各类外界刺激时，限制肺泡炎症、维持高效气体交换的生理需求相一致。然而，AM对T细胞衍生细胞因子信号的应答机制仍有待阐明——这类信号是抵御吸入性病原体的关键环节。例如，肺巨噬细胞对结核分枝杆菌（Mycobacterium tuberculosis, Mtb）的有效清除，高度依赖Th1淋巴细胞分泌的干扰素γ（IFN-γ），但AM中IFN-γ应答的蛋白质组学特征仍鲜为人知。
本研究检测了人源AM与自体外周血单核细胞（autologous blood monocytes, MN）中IFN-γ诱导的蛋白质丰度变化。经IFN-γ刺激活化后，AM可发生STAT1磷酸化，并产生MIG/CXCL9趋化因子。但相较于MN，AM对IFN-γ的全局蛋白质组学应答受到显著限制（差异丰度蛋白分别为9个AM vs 89个MN）。AM的低应答性无法通过JAK-STAT1信号通路减弱或细胞因子信号转导抑制因子1（SOCS1）表达升高来解释。上述研究结果提示，AM对IFN-γ的应答受到严格调控，这一特性既可避免过度肺部炎症，也可能为Mtb及其他肺内胞内病原体的初始定植与增殖提供适宜微环境。