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DNA-triggered innate immune responses are propagated by gap junction communication

Patel, Suraj J., King, Kevin R., Casali, Monica, Yarmush, Martin L.
Proceedings of the National Academy of Sciences of the United States of America 2009 v.106 no.31 pp. 12867-12872
DNA, gap junctions, image analysis, immune response, innate immunity, pathogens, signal transduction, tumor necrosis factor-alpha
Cells respond to infection by sensing pathogens and communicating danger signals to noninfected neighbors; however, little is known about this complex spatiotemporal process. Here we show that activation of the innate immune system by double-stranded DNA (dsDNA) triggers intercellular communication through a gap junction-dependent signaling pathway, recruiting colonies of cells to collectively secrete antiviral and inflammatory cytokines for the propagation of danger signals across the tissue at large. By using live-cell imaging of a stable IRF3-sensitive GFP reporter, we demonstrate that dsDNA sensing leads to multicellular colonies of IRF3-activated cells that express the majority of secreted cytokines, including IFNβ and TNFα. Inhibiting gap junctions decreases dsDNA-induced IRF3 activation, cytokine production, and the resulting tissue-wide antiviral state, indicating that this immune response propagation pathway lies upstream of the paracrine action of secreted cytokines and may represent a host-derived mechanism for evading viral antiinterferon strategies.