Sensitisation of colonic nociceptors by IL-13 is dependent on JAK and p38 MAPK activity.

Source: Am J Physiol Gastrointest Liver Physiol 2023 Feb 07; . doi: 10.1152/ajpgi.00280.2022Authors: Barker KH, Higham JP, Pattison LA, Chessall IP, Welsh F, Smith ESJ, Bulmer DC

The effective management of visceral pain is a significant unmet clinical need for those affected by gastrointestinal diseases, such as inflammatory bowel disease (IBD). The rational design of novel analgesics requires a greater understanding of the mediators and mechanisms underpinning visceral pain. Interleukin-13 (IL-13) production by immune cells residing in the gut is elevated in IBD, and IL-13 appears to be important in the development of experimental colitis. What’s more, receptors for IL-13 are expressed by neurons innervating the colon, though it is not known whether IL-13 plays any role in visceral nociception per se. To resolve this, we employed Ca imaging of cultured sensory neurons and ex vivo electrophysiological recording from the lumbar splanchnic nerve innervating the distal colon. Ca imaging revealed the stimulation of small-diameter, capsaicin-sensitive sensory neurons by IL-13, indicating that IL-13 likely stimulates nociceptors. IL-13-evoked Ca signals were attenuated by inhibition of Janus (JAK) and p38 kinases. In the lumbar splanchnic nerve, IL-13 did not elevate baseline firing, nor sensitise the response to capsaicin application, but did enhance the response to distention of the colon. In line with Ca imaging experiments, IL-13-mediated sensitisation of the afferent response to colon distention was blocked by inhibition of either JAK or p38 kinase signalling. Together, these data highlight a potential role for IL-13 in visceral nociception and implicate JAK and p38 kinases in pro-nociceptive signalling downstream of IL-13.

Pubmed ID: https://pubmed.ncbi.nlm.nih.gov/36749569/