Multimodal transcriptomics and calcium imaging reveal a novel subset of polymodal nociceptors expressing the interleukin 1 receptor in mice

We also demonstrated that deletion of the IL-1 receptor type 1 gene, Il1r1, in TRPV1-expressing (+) neurons prevented pain in models of chronic inflammatory diseases such as multiple sclerosis, rheumatoid arthritis and osteoarthritis. Here, we found a marked sex difference in the abundance of IL-1R1+ neurons, which represented approximately 10% of all DRG neurons in females but only 5% in males.

However, male mice exhibited stronger, longer-lasting mechanical hypersensitivity than females after IL-1β injection into the cerebrospinal fluid. In vivo calcium imaging revealed that IL-1β-responsive DRG neurons responded to cutaneous mechanical and capsaicin stimulation. By integrating spatial transcriptomics with single-cell RNA sequencing (scRNA-Seq), we identified a gene signature uniquely marking IL-1R1+ neurons, including genes such as Ada, Cysltr2, Gpr139, Htr1a, Htr1f, Il31ra, Nppb, Npy2r, Nts, P2rx2, Pde4c, and Sst, with Ada and Sst validated at the protein level.