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

• Published in: Scientific reports Vol. 14; no. 1; p. 9051
• Main Authors: Salib, Anne-Mary N., Crane, Meredith J., Lee, Sang Hun, Wainger, Brian J., Jamieson, Amanda M., Lipscombe, Diane
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.04.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/371; 631/378/1959; 631/378/2586; 631/378/371; Calcium channels (voltage-gated); Capsaicin; Capsaicin receptors; Channel gating; Cytokines; Heat; Humanities and Social Sciences; Hypersensitivity; Inflammation; Mechanical stimuli; multidisciplinary; Nerve endings; Science; Science (multidisciplinary); Sensory neurons; Skin
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-59424-6

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 Ca V 2.2 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 Ca V 2.2 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.