Dorsal root ganglion macrophages as novel target for the treatment of chronic visceral pain

Obiettivo

Chronic abdominal pain is a major symptom of irritable bowel syndrome (IBS), a gastrointestinal disorder that, depending on the diagnostic criteria used, affects 4 to 20% of the population, with a female to male ratio of 2. It is characterized by altered bowel habits associated with abdominal pain in the absence of an organic cause. Despite its high prevalence and significant impact on quality of life, insight in its pathophysiology is rather limited. Consequently, treatment is disappointing and restricted to efforts aimed at correcting altered defecation, however this approach leaves abdominal pain largely unaffected. Pain arising from the gastrointestinal tract is detected by afferent nerve fibres with their cell bodies located in the dorsal root ganglia (DRG). My team recently discovered that mast cell activation in response to food intake results in the release of histamine, which renders DRG neurons more excitable leading to increased pain signalling, also referred to as visceral hypersensitivity (VHS). The clinical relevance of this finding is supported by the observation that treatment with antihistamines improves abdominal pain in about 50% of IBS patients. In MACPAIN, I aim to discover new therapeutic targets to treat the remaining 50%. Of interest, DRG neurons are surrounded by resident macrophages with which they closely interact. I hypothesize that repetitive peripheral activation of DRG neurons leads to the release of macrophage modulating mediators ultimately leading to persistent alterations in resident macrophage function and chronic VHS. Using state-of-the-art methods, we will first interrogate the impact of repetitive afferent nerve activation on the DRG macrophage population to subsequently unravel the mechanisms leading to chronic VHS. These groundbreaking insights will allow us to identify novel therapeutic targets to treat chronic VHS and will pave the way for the development of new therapeutic compounds for IBS.