Macrophage Epithelial Reprogramming Underlies Mycobacterial Granuloma Formation and Promotes Infection

Abstract

SUMMARY Mycobacterium tuberculosis infection in humans triggers formation of granulomas, 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.

Heterogeneity in tuberculosis

“…Very recent work in our laboratories has confirmed these findings, demonstrating that only a subset of granulomas disseminate to form new, productive granulomas and showing that granuloma size at 4–5 weeks post infection correlates with dissemination 69 . Recent work in the zebrafish– Mycobacterium marinum model has identified similar crucial events in granuloma formation and organization that depend on the macrophage-specific reprogramming of adhesion pathways that are dependent on epithelial cadherin (E-cadherin; also known as cadherin 1) 70 . Disruption of this axis resulted in disordered granuloma formation and increased host clearance following increased neutrophil access.…”

Angiotensin-converting enzyme in innate and adaptive immunity

“…55). Macrophages within the granuloma were reported to have an approximately sevenfold increase in ACE mRNA compared with kidney macrophages in a zebrafish model of Mycobacterium marinum infection, in which detailed cellular events that characterize granuloma formation can be visualized 56 . Fluorescence imaging and electron microscopy showed that forming granulomas undergo macrophage reprogram ming to express adherens-type cellular proteins, such as epithelial cadherin (E-cadherin; also known as CDH1), which are more typical of epithelial cells than myeloid cells, thereby allowing macrophages to form cell–cell contacts.…”

A whole animal chemical screen approach to identify modifiers of intestinal neutrophilic inflammation

“…The convergence of inflammation‐modifying hits onto the dopamine and CCK receptor signaling pathways was useful for the purpose of prioritizing compounds for further investigation. Expression profiling datasets (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE12189 and http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE81913) demonstrate expression of dopamine and CCK receptors by zebrafish leukocytes and intestinal epithelial cells . Our infection experiments where cabergoline had an immunosuppressive effect in a model of systemic infection suggest a direct effect of dopamine receptor manipulation on zebrafish leukocytes.…”