Protease-activated receptor 1-mediated matrix metalloprotease signalling in sensory neurons

Visceral pain is a prevalent and debilitating symptom of inflammatory bowel disease (IBD). However, current pain therapies are often ineffective, raising the possibility that novel disease mediators might be contributing to pain during inflammation. Our study provides new insights into how matrix metalloproteinases (MMPs), which are elevated in IBD, stimulate sensory neurons. We demonstrate that MMP3, MMP8, and MMP9 induce intracellular Ca ²⁺ release in dorsal root ganglion (DRG) neurons through activation of protease-activated receptor 1 (PAR1) and subsequent activation of phospholipase C (PLC). Characterisation of the neuronal populations stimulated by these MMPs suggests that a subset is likely nociceptive. In contrast, MMP2 and MMP13, although capable of cleaving PAR1 in other cell types, do not induce Ca ²⁺ mobilisation in DRG neurons. Interestingly, pre-treatment with MMP2 or MMP13 reduces the neuronal response to MMP3 or PAR1 agonist, suggesting that MMP2 and MMP13 act on PAR1 in a manner which prevents further activation. Additionally, MMP10 induces Ca ²⁺ mobilisation in DRG neurons but through a PAR1-independent mechanism. These findings uncover a previously unrecognised role for MMP signalling in sensory neurons, highlighting a potential mechanism by which MMPs could contribute to the pro-nociceptive environment in the inflamed bowel.