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 Article has an altmetric score of 18

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 7

KChIP1/Kv4 interaction promotes the anti-nociceptive effect of ISGs.

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KChIP1/Kv4 interaction promotes the anti-nociceptive effect of ISGs. (A)...
(A) Representative current clamp recording of TRPV1cre-GOF neurons, in control condition and after AmmTx3 (1 μM) application (top). Cells were injected with 500-millisecond current pulses with an increment of 10 pA and an interval of 5 seconds (protocol, bottom). The highlighted black line indicates the current amplitude that induces the first AP. Scale bars: 20 mV/50 ms. (B and C) Measurement of rheobase (B) and AP half-width (C) induced by AmmTx3 application in TRPV1cre-GOF neurons (n = 29 neurons). (D) Representative outward potassium currents recorded in response to voltage steps in TRPV1cre-GOF, in control condition and after AmmTx3 application. Scale bars: 1 nA/100 ms. (E) Average current-voltage relationship obtained from the cells recorded in D (n = 9). (F) Representative current clamp recording of TRPV1cre-GOF neurons treated with a TAT-conjugated KChIP1 peptide for 40 minutes (top). Cells were injected with 500-millisecond current pulses with an increment of 10 pA and an interval of 5 seconds (protocol, bottom). The highlighted black line indicates the current amplitude that induces the first AP. Scale bars: 20 mV/50 ms. (G) Time-dependent effect of TAT-conjugated KChIP1 versus denatured control peptide on the rheobase of TRPV1Cre-GOF neurons (n = 15 and 17, respectively) and GOF control neurons (n = 10 and 11, respectively). (H) Measurement of rheobase at t = 0 and 45 minutes after KChIP1 exposure or denatured peptide in TRPV1cre-GOF neurons (TAT-Denat, n = 15; TAT-KChIP1, n = 17) or GOF neurons (TAT-Denat, n = 10; TAT-KChIP1, n = 12). (I) Measurement of thermal withdrawal latency in hind paws of both CFA-treated GOF and TRPV1cre-GOF mice treated with 5 μg (n = 7, 7) or 10 μg (n = 6, 7) KChIP1 blocking peptide or its denatured control (n = 6, 7) at day 3 after CFA injection. Statistical analysis was performed using paired t test (B, C, and H) and 2-way ANOVA followed by Tukey’s post hoc test (E and I; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001).