Extended Data Fig. 10: dsDNA induces antinociception via the cGAS/STING/IFN-I pathway and proposed mechanism of STING/IFN-I regulation of nociception.
From: STING controls nociception via type I interferon signalling in sensory neurons
a, i.t. IFN-α and IFN-β elevated mechanical thresholds in WT mice and could transiently rescue the mechanical hypersensitivity phenotype of STINGgt/gt mice back to levels comparable to WT baseline levels. b, Schematic illustrating intracellular poly(dA:dT) induces cGAS/STING-dependent IFN-I upregulation whereas intracellular poly(I:C) induces IFN-I response through a STING-independent mechanism. c, d, Mice of the indicated genotypes were administered 1 μg poly(I:C) or 1 μg poly(dA:dT) via i.t. injection followed by Von Frey testing to determine mechanical thresholds at the indicated time points. c, Intrathecal poly(I:C) elevated mechanical thresholds in Ifnar1fl/fl (WT), STINGgt/gt, and cGAS−/− mice, but these effects were abolished in Ifnar1fl/fl;Nav1.8-Cre and RIG-I−/− mice. d, Intrathecal poly(dA:dT) elevated mechanical thresholds in WT and RIG-I−/− mice for up to 24 h, but these effects were abolished in Ifnar1fl/fl;Nav1.8-Cre, STINGgt/gt, and cGAS−/− mice. e–g, Sodium currents were recorded from DRG nociceptors cultured from Ifnar1+/+ or Ifnar1−/− mice, perfused with vehicle or IFN-I for 2 min as indicated. Representative traces (e) and quantification (f) of Na+ currents demonstrating that rIFN-I treatment led to a reduction in sodium currents. g, Nociceptors from Ifnar1-gKO mice exhibited increased Na+ current amplitude at baseline. h, i, HEK293 cells stably expressing the voltage-gated sodium channel Nav1.7 were perfused as in panel f and Na+ currents were recorded. Representative traces (h) and Timecourse (i) of Nav1.7-mediated currents. IFN-I perfusion reduced Nav1.7-mediated currents. All data are expressed as the mean ± s.e.m. *P < 0.05; **P < 0.01; ***P < 0.001, ****P < 0.0001. Statistical comparisons were conducted with two-way ANOVA with Dunnett’s post hoc test (a, c, d), two-way ANOVA with Bonferroni’s post hoc test (f, i), or two-tailed t-test (g). See Supplementary Information for complete sample sizes, sex, and statistical information.
