Interleukin-1α links peripheral CaV2.2 channel activation to rapid adaptive increases in heat sensitivity in skin

Abstract

Neurons have the unique capacity to adapt output in response to changes in their environment. Within seconds, sensory nerve endings can become hypersensitive to stimuli in response to potentially damaging events. The underlying behavioral response is well studied, but several of the key signaling molecules that mediate sensory hypersensitivity remain unknown. We previously discovered that peripheral voltage-gated CaV2.2 channels in nerve endings in skin are essential for the rapid, transient increase in sensitivity to heat, but not to mechanical stimuli, that accompanies intradermal capsaicin. Here we report that the cytokine interleukin-1α (IL-1α), an alarmin, is necessary and sufficient to trigger rapid heat and mechanical hypersensitivity in skin. Of 20 cytokines screened, only IL-1α was consistently detected in hind paw interstitial fluid in response to intradermal capsaicin and, similar to behavioral sensitivity to heat, IL-1α levels were also dependent on peripheral CaV2.2 channel activity. Neutralizing IL-1α in skin significantly reduced capsaicin-induced changes in hind paw sensitivity to radiant heat and mechanical stimulation. Intradermal IL-1α enhances behavioral responses to stimuli and, in culture, IL-1α enhances the responsiveness of Trpv1-expressing sensory neurons. Together, our data suggest that IL-1α is the key cytokine that underlies rapid and reversible neuroinflammatory responses in skin.

Peripheral CaV2.2 channels in skin regulate prolonged heat hypersensitivity during neuroinflammation

“…1b). These data, combine with previous studies using the capsaicin model of rapidly developing and transient heat hypersensitivity (DuBreuil et al, 2021;Salib et al, 2024), show that CaV2.2 channels have a privileged and specific role in neuroimmune signaling that triggers long lasting heat hypersensitivity in skin. By contrast, CFA-induced mechanical hypersensitivity and paw edema developed and were maintained by signaling pathways that were independent of CaV2.2 channels.…”

“…To establish the contribution of CaV2.2 channels to these behavioral responses we assessed the effects of id CFA in a CaV2.2 knockout strain (CaV2.2 -/-KO) (DuBreuil et al, 2021;Salib et al, 2024) and WT mice injected with id ⍵-CgTx MVIIA (Fig. 1).…”

“…The CaV2.2 -/global deletion (CaV2.2 -/-KO) mouse strain used in these studies (Cacna1b tm5.1DiLi ; MGI). contains a STOP cassette in frame, in exon 1 of Cacna1b and has been described previously (DuBreuil et al, 2021;Salib et al, 2024). Control mice for comparison to the CaV2.2 -/-KO strain were either littermate controls (in all immunophenotyping experiments) or wild-type mice which have been bred in-house in parallel with, and from the same genetic background as Ca V 2.2 -/-KO.…”

“…A single dose of -CgTx MVIIA, applied intradermally together with capsaicin, specifically prevents the rapid development of heat hypersensitivity without affecting cross-sensitization of mechanoreceptors in the same animals (DuBreuil et al, 2021). IL-1ɑ, an early released proinflammatory alarmin, couples CaV2.2 channel activity to increased excitability of Trpv1 nociceptors (Salib et al, 2024). Interfering with the activity of IL-1 using a neutralizing antibody significantly reduces capsaicin-induced inflammatory hypersensitivity to both heat and mechanical stimuli (Salib et al, 2024).…”

“…IL-1ɑ, an early released proinflammatory alarmin, couples CaV2.2 channel activity to increased excitability of Trpv1 nociceptors (Salib et al, 2024). Interfering with the activity of IL-1 using a neutralizing antibody significantly reduces capsaicin-induced inflammatory hypersensitivity to both heat and mechanical stimuli (Salib et al, 2024).…”