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

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. Whats 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 Ca2+ imaging of cultured sensory neurons and ex vivo electrophysiological recording from the lumbar splanchnic nerve innervating the distal colon. Ca2+ imaging revealed the stimulation of small-diameter, capsaicin-sensitive sensory neurons by IL-13, indicating that IL-13 likely stimulates nociceptors. IL-13-evoked Ca2+ 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 Ca2+ 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. Key Points SummaryThe pro-inflammatory cytokine IL-13 is elevated in gastrointestinal (GI) diseases and known to sensitise sensory neurons. This study confirms a role for IL-13 in colonic afferent sensitisation and defines a role for downstream JAK and p38 MAPK signalling in colonic mechanosensitisation. IL-13-mediated increase in [Ca2+]i in capsaicin-sensitive sensory neurons is dependent on p38 MAPK and JAK signalling. IL-13-induced sensitisation of colonic afferents to noxious mechanical distension is abolished by inhibition of p38 MAPK and JAK. We have built on the current understanding of IL-13 and its neuronal interactions, highlighting the therapeutic potential of targeting p38 MAPK and JAK signalling pathways to treat visceral pain in GI disease.