DNA-triggered innate immune responses are propagated by gap junction communication.
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 IFNbeta and TNFalpha. 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.
Patel
Suraj J
SJ
Department of Surgery, Center for Engineering in Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
King
Kevin R
KR
Casali
Monica
M
Yarmush
Martin L
ML
D000818:Animals; D002450:Cell Communication; D002478:Cells, Cultured; D004247:DNA / Q000494:pharmacology*; D017629:Gap Junctions / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000209:etiology; D050838:Interferon Regulatory Factor-3 / Q000502:physiology; D051379:Mice
C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D004247:DNA