Petursdottir Dagbjort H, Chuquimia Olga D, Freidl Raphaela, Fernández Carmen
Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
PLoS One. 2014 Aug 4;9(8):e103411. doi: 10.1371/journal.pone.0103411. eCollection 2014.
Tissue-resident macrophages are heterogeneous with tissue-specific and niche-specific functions. Thus, simplified models of macrophage activation do not explain the extent of heterogeneity seen in vivo. We focus here on the respiratory tract and ask whether factors secreted by alveolar epithelial cells (AEC) can influence the functionality of resident pulmonary macrophages (PuM). We have previously reported that factors secreted by AEC increase control of intracellular growth of BCG in macrophages. In the current study, we also aimed to investigate possible mechanisms by which AEC-derived factors increase intracellular control of BCG in both primary murine interstitial macrophages, and bone marrow-derived macrophages and characterize further the effect of these factors on macrophage differentiation. We show that; a) in contrast to other macrophage types, IFN-γ did not increase intracellular growth control of Mycobacterium bovis, Bacillus Calmette-Guérin (BCG) by interstitial pulmonary macrophages although the same macrophages could be activated by factors secreted by AEC; b) the lack of response of pulmonary macrophages to IFN-γ was apparently regulated by suppressor of cytokine signaling (SOCS)1; c) AEC-derived factors did not induce pro-inflammatory pathways induced by IFN-γ e.g. expression of inducible nitric oxide synthase (iNOS), secretion of nitric oxide (NO), or IL-12, d) in contrast to IFN-γ, intracellular bacterial destruction induced by AEC-derived factors was not dependent on iNOS transcription and NO production. Collectively, our data show that PuM were restricted in inflammatory responses mediated by IFN-γ through SOCS1 and that factors secreted by AEC- enhanced the microbicidal capacities of macrophages by iNOS independent mechanisms.
组织驻留巨噬细胞具有异质性，具有组织特异性和生态位特异性功能。因此，巨噬细胞激活的简化模型无法解释体内观察到的异质性程度。我们在此聚焦于呼吸道，探讨肺泡上皮细胞（AEC）分泌的因子是否会影响肺部驻留巨噬细胞（PuM）的功能。我们之前报道过，AEC分泌的因子可增强巨噬细胞对卡介苗细胞内生长的控制。在当前研究中，我们还旨在探究AEC衍生因子增强原代小鼠间质巨噬细胞和骨髓来源巨噬细胞对卡介苗细胞内控制的可能机制，并进一步表征这些因子对巨噬细胞分化的影响。我们发现：a）与其他巨噬细胞类型不同，干扰素-γ（IFN-γ）不会增强肺间质巨噬细胞对牛分枝杆菌卡介苗（BCG）的细胞内生长控制，尽管相同的巨噬细胞可被AEC分泌的因子激活；b）肺巨噬细胞对IFN-γ缺乏反应显然受细胞因子信号转导抑制因子（SOCS）1调控；c）AEC衍生因子不会诱导IFN-γ诱导的促炎途径，如诱导型一氧化氮合酶（iNOS）的表达、一氧化氮（NO）的分泌或白细胞介素-12；d）与IFN-γ相反，AEC衍生因子诱导的细胞内细菌破坏不依赖于iNOS转录和NO产生。总体而言，我们的数据表明，PuM在通过SOCS1介导的IFN-γ炎症反应中受到限制，并且AEC分泌的因子通过不依赖iNOS的机制增强了巨噬细胞的杀菌能力。
