Reduction of Silent Information Regulator 1 Activates Interleukin-33/ST2 Signaling and Contributes to Neuropathic Pain Induced by Spared Nerve Injury in Rats

Abstract

Emerging studies have demonstrated that interleukin (IL)-33 and its receptor ST2 act as key factors in inflammatory diseases. Moreover, accumulating evidence has suggested that cytokines, including tumor necrosis factor (TNF)-α and IL-1β, trigger an inflammatory cascade. SIRT1 has been shown to suppress the expression of inflammatory cytokines. However, the effects of SIRT1 on IL-33/ST2 signaling and initiation of the inflammatory cascade via modulation of TNF-α and IL-1β by IL-33 remain unclear. In the present study, we found that the dorsal root ganglion (DRG) IL-33 and ST2 were upregulated in a rat model of spared nerve injury (SNI) and intrathecal injection of either IL-33 or ST2 antibodies alleviated mechanical allodynia and downregulated TNF-α and IL-1β induced by SNI. In addition, activation of SIRT1 decreased enhanced DRG IL-33/ST2 signaling in SNI rats. Artificial inactivation of SIRT1 via intrathecal injection of an SIRT1 antagonist could induce mechanical allodynia and upregulate IL-33 and ST2. These results demonstrated that reduction in SIRT1 could induce upregulation of DRG IL-33 and ST2 and contribute to mechanical allodynia induced by SNI in rats.

Red nucleus IL-33 facilitates the early development of mononeuropathic pain in male rats by inducing TNF-α through activating ERK, p38 MAPK, and JAK2/STAT3

“…The latest studies have shown that IL-33 regulates the transcription of proinflammatory cytokines [ 44 , 54 ]. It has been reported that IL-33 facilitates pathological pain by stimulating the secretion of TNF-α, IL-1β, and/or IL-6 [ 31 , 38 – 40 ]. In the current study, red nucleus IL-33 begins to increase at 3 days post-SNI, reaches to peak at 1 week, and returns to normal level at 2 weeks.…”

Puerarin Attenuates Complete Freund’s Adjuvant-Induced Trigeminal Neuralgia and Inflammation in a Mouse Model via Sirt1-Mediated TGF-β1/Smad3 Inhibition

“… 48 Recently, Sirt1 was shown to participate in neuroprotection, wound healing and anti-inflammation. 49 , 50 Sirt1 is profoundly inhibited in trigeminal sensory neurons that exhibit hyperglycemia-induced nerve injury. 49 In a rat model of spared nerve injury, the production of inflammatory cytokines was inhibited by Sirt1.…”

“… 49 In a rat model of spared nerve injury, the production of inflammatory cytokines was inhibited by Sirt1. 50 A growing number of evidence suggests that Sirt1 is a key gene and therapeutic target for improving neuropathic pain in various animal models. 26 , 30 For example, Sirt1 activators mitigate hyperalgesia and spinal neuronal activation in diabetic neuropathic pain rats.…”

Interleukin 33-mediated inhibition of A-type K+ channels induces sensory neuronal hyperexcitability and nociceptive behaviors in mice

“…Recent evidence has also suggested a functional role of IL-33/ST2 in nociceptive pain behaviors 8 - 13 . For instance, it has been demonstrated that IL-33 and its receptor ST2 in the DRG were upregulated in a rat model of spared nerve injury (SNI), and intrathecal injection of either an IL-33 antagonist or a neutralizing antibody to ST2 alleviated mechanical allodynia 13 , 14 . Moreover, genetic deletion of ST2 resulted in amelioration of pain hypersensitivity in a mouse model of gout 15 .…”