title: Macrophage control of phagocytosed mycobacteria is increased by factors secreted by alveolar epithelial cells through nitric oxide independent mechanisms.
abstract: 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.
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Dagbjort H
authors.initials: DH
authors.lastname: Petursdottir
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Olga D
authors.initials: OD
authors.lastname: Chuquimia
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Raphaela
authors.initials: R
authors.lastname: Freidl
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Carmen
authors.initials: C
authors.lastname: Fernández
mesh_terms: D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002738:Chloroquine / Q000494:pharmacology; D005260:Female; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000235:genetics; D042541:Intracellular Space / Q000187:drug effects / Q000382:microbiology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009161:Mycobacterium / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D009163:Mycobacterium bovis / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D053583:Interleukin-1beta; D017382:Reactive Oxygen Species; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D009569:Nitric Oxide; D007371:Interferon-gamma; D002738:Chloroquine; D052247:Nitric Oxide Synthase Type II
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