Macrophage Epithelial Reprogramming Underlies Mycobacterial Granuloma Formation and Promotes Infection

• Published in: Immunity (Cambridge, Mass.) Vol. 45; no. 4; pp. 861 - 876
• Main Authors: Cronan, Mark R., Beerman, Rebecca W., Rosenberg, Allison F., Saelens, Joseph W., Johnson, Matthew G., Oehlers, Stefan H., Sisk, Dana M., Jurcic Smith, Kristen L., Medvitz, Neil A., Miller, Sara E., Trinh, Le A., Fraser, Scott E., Madden, John F., Turner, Joanne, Stout, Jason E., Lee, Sunhee, Tobin, David M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.10.2016; Elsevier Limited
• Subjects: Animals; Cadherins - immunology; Epithelium - immunology; Epithelium - microbiology; Experiments; Granuloma - immunology; Granuloma - microbiology; Histology; Immunoglobulins; Infections; Keratin; Laboratories; Macrophages - immunology; Macrophages - microbiology; Microscopy; Mycobacterium marinum - immunology; Mycobacterium tuberculosis; Mycobacterium tuberculosis - immunology; Pathology; Tuberculosis; Zebrafish
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2016.09.014

Mycobacterium tuberculosis infection in humans triggers formation of granulomas, which are tightly organized immune cell aggregates that are the central structure of tuberculosis. Infected and uninfected macrophages interdigitate, assuming an altered, flattened appearance. Although pathologists have described these changes for over a century, the molecular and cellular programs underlying this transition are unclear. Here, using the zebrafish-Mycobacterium marinum model, we found that mycobacterial granuloma formation is accompanied by macrophage induction of canonical epithelial molecules and structures. We identified fundamental macrophage reprogramming events that parallel E-cadherin-dependent mesenchymal-epithelial transitions. Macrophage-specific disruption of E-cadherin function resulted in disordered granuloma formation, enhanced immune cell access, decreased bacterial burden, and increased host survival, suggesting that the granuloma can also serve a bacteria-protective role. Granuloma macrophages in humans with tuberculosis were similarly transformed. Thus, during mycobacterial infection, granuloma macrophages are broadly reprogrammed by epithelial modules, and this reprogramming alters the trajectory of infection and the associated immune response. [Display omitted] •Macrophages mobilize classical epithelial modules during granuloma formation•Macrophage reprogramming shares features of mesenchymal-epithelial transitions•Inhibition of macrophage epithelialization leads to disordered granulomas•Granuloma disruption increases immune access and promotes host survival A hallmark of tuberculosis is aggregation of macrophages into a structure termed the granuloma. Cronan et al. show that macrophages deploy classical epithelialization pathways to construct mycobacterial granulomas. This reprogramming is host detrimental, as macrophage-specific inhibition of the process enhances host survival and immune cell access and reduces bacterial burden.