Patel Suraj J, King Kevin R, Casali Monica, Yarmush Martin L
Department of Surgery, Center for Engineering in Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12867-72. doi: 10.1073/pnas.0809292106. Epub 2009 Jul 17.
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.
细胞通过感知病原体并向未感染的邻近细胞传递危险信号来应对感染；然而，对于这一复杂的时空过程我们知之甚少。在这里，我们表明双链DNA（dsDNA）激活先天免疫系统会通过依赖于间隙连接的信号通路触发细胞间通讯，募集细胞集落以集体分泌抗病毒和炎性细胞因子，从而使危险信号在整个组织中传播。通过对稳定的IRF3敏感GFP报告基因进行活细胞成像，我们证明dsDNA感应会导致IRF3激活的细胞形成多细胞集落，这些细胞表达大多数分泌的细胞因子，包括IFNβ和TNFα。抑制间隙连接会降低dsDNA诱导的IRF3激活、细胞因子产生以及由此产生的全组织抗病毒状态，表明这种免疫反应传播途径位于分泌细胞因子旁分泌作用的上游，可能代表了宿主逃避病毒抗干扰素策略的一种机制。
