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

Abstract

Background: Interleukin-33 (IL-33) has been implicated in nociceptive pain behaviors. However, the underlying molecular and cellular mechanisms remain unclear. Methods: Using electrophysiological recording, immunoblot analysis, immunofluorescence labeling, reverse transcription-PCR, siRNA-mediated knockdown approach and behavior tests, we determined the role of IL-33 in regulating sensory neuronal excitability and pain sensitivity mediated by A-type K + channels. Results: IL-33 decreased A-type transient outward K + currents ( I A ) in small-sized DRG neurons in a concentration-dependent manner, whereas the delayed rectifier currents ( I DR ) remained unaffected. This IL-33-induced I A decrease was dependent on suppression of the tumorigenicity 2 (ST2) receptor and was associated with a hyperpolarizing shift in the steady-state inactivation. Antagonism of Syk abrogated the IL-33-induced I A response, while inhibition of JAK2 and PKA elicited no such effect. Exposure of DRG cells to IL-33 increased the activity of Akt, but surprisingly, neither Akt nor PI3K influenced the IL-33-induced I A response. IL-33 increased the level of phosphorylated p38 mitogen-activated protein kinase (MAPK). Chemical inhibition of p38 and genetic siRNA knockdown of p38 beta (p38β), but not p38α, abrogated the I A response induced by IL-33. Moreover, IL-33 increased neuronal excitability of DRG neurons and facilitated peripheral pain sensitivity in mice; both of these effects were occluded by I A blockade. Conclusions: Our present study reveals a novel mechanism by which IL-33/ST2 suppresses I A via a Syk-dependent p38β signaling pathway. This mechanism thereby increases DRG neuronal excitability and pain sensitivity in mice. Targeting IL-33/ST2-mediated p38β signaling may represent a therapeutic approach to ameliorate pain behaviors.

Adiponectin receptor 1-mediated stimulation of Cav3.2 channels in trigeminal ganglion neurons induces nociceptive behaviors in mice

“…Currents were recorded at -40 mV by 40 ms depolarizing pulses from a holding potential of -110 mV. The two kinetically distinct Kv currents, I A and I DR, were separated following our previous protocols [ 30 , 31 ]. Typical Kv currents exhibited transient components followed by slowly decaying and sustained components.…”

The role of IL-33 in depression: a systematic review and meta-analysis

“…Moreover, IL-33 mRNA's expression is upregulated in neurons and astrocytes following subarachnoid hemorrhage (26). External stress, emotional stress, and internal inflammatory stimuli can lead to upregulation of IL-33 expression in the brain, as inflammatory stimuli such as PAMPs (LPS, dsRNA, PAMPs + ATP) induce the production of pro-inflammatory cytokines by microglial cells and mast cells (27). Studies have shown that cytokines can influence the pathogenesis of depression through changes in biogenic amine metabolism in the midbrain nucleus such as dopamine, norepinephrine, and serotonin (28).…”

IGF/IGF-1R signal pathway in pain: a promising therapeutic target

“…Lin et al also found that the expression of Cav3.2 and IGF-1R in lumbar DRG was up-regulated after sciatic neurotomy, indicating the interaction of T-type Cav3.2 channel and IGF-1 can contribute to pain hypersensitivity in primary sensory nerves 100 . Besides, there are two main types of outward voltage gated K + channel (Kv) currents in nociceptive neurons to induced pain: I A and I DR 101 - 103 . Bath application of IGF-1 (0.1 μM) inhibited I A in small TG neurons.…”