Induction of antiviral interferon-stimulated genes by neuronal STING promotes the resolution of pain in mice
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
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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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 5

ISGs alter nociceptor properties through TRPV1 downregulation and KChIP1 expression.

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ISGs alter nociceptor properties through TRPV1 downregulation and KChIP1...
(A) Representative current clamp recording of evoked action potentials (APs) recorded in TRPV1 neurons (top). Cells were injected with a 500-millisecond current pulse 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) Rheobase data recorded in TRPV1 and non-peptidergic (IB4+) neurons from GOF (n = 61 and n = 16, respectively) and TRPV1cre-GOF mice (n = 101 and n = 22, respectively). (C) Number of spikes as a function of injected current in TRPV1 neurons. (D) Representative APs recorded in TRPV1 neurons from GOF (n = 61) and TRPV1cre-GOF (n = 101) mice. Scale bars: 20 mV/50 ms. (E) AP half-width recorded in D. (F) Representative currents induced by capsaicin (100 nM) in TRPV1 neurons. Scale bars: 200 pA/10 s. (G) Current density evoked by capsaicin in TRPV1 neurons from GOF (n = 25) and TRPV1cre-GOF (n = 70) mice. (H) Representative Western blot of KChIP1 protein level. Three independent experiments were performed. (I) Quantification of KChIP1 protein level in lumbar DRG from naive GOF (n = 5) and TRPV1cre-GOF (n = 5) mice. (J) Representative outward potassium currents recorded in response to voltage steps in TRPV1 neurons. Scale bars: 1 nA/100 ms. (K) Average current-voltage relationship from neurons recorded in J (GOF, n = 10; TRPV1cre-GOF, n = 17). (L and M) Steady-state activation (L) and inactivation (M) from neurons recorded in J (activation: GOF, n = 17; TRPV1cre-GOF, n = 17; inactivation: GOF, n = 18; TRPV1cre-GOF, n = 25). All steady-state plots were fitted with Boltzmann functions to derive V½ and k values. Statistical analysis was performed using Kruskal-Wallis followed by Dunn’s post hoc test (B; ****P < 0.0001), 2-way ANOVA followed by Tukey’s post hoc test (C and K–M; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001), and Mann-Whitney test (E and G) or t test (I; *P < 0.05, ****P < 0.0001).