Neurochemical drivers of visceral pain: insights into the roles of interleukin-17 and the proton-sensing G protein-coupled receptor GPR68

People with inflammatory bowel disease (IBD) often experience severe abdominal pain that remains poorly managed due to limited therapeutic options and the gut-related side effects of conventional analgesics. My thesis addresses this unmet clinical need by investigating inflammatory mediators and mechanisms that drive pain in the gut, with a focus on interleukin 17 (IL-17) and the proton-sensing G protein-coupled receptor (GPCR) GPR68. In the first part of my research, I identified IL-17 as a pro-nociceptive cytokine. This was based on transcriptomic data showing elevated IL17A expression in colonic biopsies from individuals with IBD and co-expression of its receptor, Il17ra, with the nociceptor marker Trpv1 in murine colon-projecting sensory neurons. Using Ca2+-imaging of dorsal root ganglion (DRG) neurons, including neuron-enriched cultures generated by magnetic-activated cell sorting, I demonstrated that IL-17 directly activates capsaicin-sensitive DRG neurons in a phosphoinositide 3-kinase (PI3K)-dependent manner. Consistent with this, IL-17 potentiated colonic afferent responses to noxious distension in ex vivo nerve preparations, an effect also abolished by PI3K inhibition. These findings establish a novel role for IL-17 in pain processing and position it as a potential therapeutic target for abdominal pain in colitis. Alongside inflammation, localised tissue acidosis driven, in part, by the heightened glycolytic activity of infiltrating immune cells, further shapes nociception in the gut. For this reason, I also investigated the role of GPR68, a proton-sensing GPCR that is upregulated in colonic biopsies from individuals with IBD, expressed by colonic nociceptors, and contributes to disease severity, as shown in an acute dextran sodium sulphate (DSS)-induced colitis model. Using GPR68 knockout mice and selective pharmacological modulators, I demonstrated that GPR68 contributes to acid-induced nociception in both in vitro and ex vivo settings. Together, my research identifies IL-17 and GPR68 as critical mediators of nociception in gastrointestinal inflammation and provides new mechanistic insight that may guide the development of more effective visceral analgesics for people with IBD.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2025

Author dc:creator

• Paine, Luke

Advisors dc:contributor.advisor

• Bulmer, David
• Smith, Ewan St John

• Nociception
• Colitis
• Cytokines
• Proton-sensing

Licence

• https://www.repository.cam.ac.uk/bitstreams/91795ae1-8c31-404f-8351-fd5ae22468c7/download
• http://purl.org/NET/rdflicense/allrightsreserved

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.127344

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/398509