Induction of antiviral interferon-stimulated genes by neuronal STING promotes the resolution of pain in mice
Manon Defaye, … , Isaac M. Chiu, Christophe Altier
Manon Defaye, … , Isaac M. Chiu, Christophe Altier
Published May 1, 2024
Citation Information: J Clin Invest. 2024;134(9):e176474. https://doi.org/10.1172/JCI176474.
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Research Article Inflammation Neuroscience

Induction of antiviral interferon-stimulated genes by neuronal STING promotes the resolution of pain in mice

Abstract

Inflammation and pain are intertwined responses to injury, infection, or chronic diseases. While acute inflammation is essential in determining pain resolution and opioid analgesia, maladaptive processes occurring during resolution can lead to the transition to chronic pain. Here we found that inflammation activates the cytosolic DNA–sensing protein stimulator of IFN genes (STING) in dorsal root ganglion nociceptors. Neuronal activation of STING promotes signaling through TANK-binding kinase 1 (TBK1) and triggers an IFN-β response that mediates pain resolution. Notably, we found that mice expressing a nociceptor-specific gain-of-function mutation in STING exhibited an IFN gene signature that reduced nociceptor excitability and inflammatory hyperalgesia through a KChIP1-Kv4.3 regulation. Our findings reveal a role of IFN-regulated genes and KChIP1 downstream of STING in the resolution of inflammatory pain.

Authors

Manon Defaye, Amyaouch Bradaia, Nasser S. Abdullah, Francina Agosti, Mircea Iftinca, Mélissa Delanne-Cuménal, Vanessa Soubeyre, Kristofer Svendsen, Gurveer Gill, Aye Ozmaeian, Nadine Gheziel, Jérémy Martin, Gaetan Poulen, Nicolas Lonjon, Florence Vachiery-Lahaye, Luc Bauchet, Lilian Basso, Emmanuel Bourinet, Isaac M. Chiu, Christophe Altier

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Figure 3

Nociceptor-specific STING-N154S gain of function reduces thermal sensitivity and heat hyperalgesia in an IFNAR1-dependent manner.

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Nociceptor-specific STING-N154S gain of function reduces thermal sensiti...
(A) Schematic representation of transgenic TRPV1cre-GOF cKI mouse design. (B and C) IFN-α (B) and IFN-β (C) levels in DRG cultures of GOF (n = 4) and TRPV1cre-GOF (n = 6) mice stimulated with ADU-S100 (1 μg/mL). (D and E) Measurement of thermal sensitivity of naive TRPV1cre-GOF (n = 15–16) and GOF (n = 7–12) mice using the hot plate (D) or Hargreaves test (E). (F) Measurement of thermal withdrawal latency in hind paws of CFA-treated GOF (n = 9) and TRPV1cre-GOF (n = 8) mice. (G) Measurement of thermal withdrawal latency in hind paws of CFA-treated TRPV1cre-GOF mice that received either IgG control (n = 5) or IFNAR1 neutralizing antibody (MAR1) before and 3 days after CFA injection (n = 6). (H) Newly born TRPV1cre-GOF pups (P5) were given 10 μL of AAV-PHP.S-DIO-IFNAR1-shRNA or AAV-PHP.S-DIO-scrambled-shRNA intraperitoneally. (I) Measurement of thermal sensitivity of mice injected with IFNAR1-Scr (n = 9) or IFNAR1-shRNA (n = 16) AAV using the hot plate. (J) Measurement of thermal withdrawal latency of CFA-treated mice infected with IFNAR1-Scr (n = 7) or IFNAR1-shRNA (n = 9) AAV. (K) Adult TRPV1cre-GOF mice received 10 μL of AAV-DIO-IFNAR1-shRNA or AAV-DIO-scrambled-shRNA intrathecally. (L) Measurement of thermal withdrawal latency in hind paws of CFA-treated mice injected with IFNAR1-Scr (n = 7) or IFNAR1-shRNA (n = 8) AAV. Statistical analysis was performed using 1-way ANOVA followed by Tukey’s post hoc test (B and C; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001); t test (E and I) or Mann-Whitney test (D; **P < 0.01, ****P < 0.0001); and 2-way ANOVA followed by Tukey’s post hoc test (F: **P < 0.01, ***P < 0.001, ****P < 0.0001 vs. TRPV1cre-GOF i.l.; G: *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 vs. TRPV1cre-GOF+IgG i.l.; J and L: *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 vs. IFNAR1-Scr i.l.; $P < 0.05, $$P < 0.01, $$$P < 0.001, $$$$P < 0.0001 vs. IFNAR1-Scr c.l.).