Protease-activated receptor 1-mediated matrix metalloprotease signaling 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 metalloproteases (MMPs), which are elevated in IBD, stimulate sensory neurons. We demonstrate that MMP3, MMP8, and MMP9 induce intracellular Ca²⁺ release in dorsal root ganglion (DRG) neurons through activation of protease-activated receptor 1 (PAR1) and subsequent activation of phospholipase C (PLC). Characterization 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 Ca²⁺ mobilization in DRG neurons. Interestingly, pretreatment with MMP2 or MMP13 reduces the neuronal response to MMP3 or TRAP6, a synthetic PAR1 agonist, suggesting that MMP2 and MMP13 act on PAR1 in a manner that prevents further activation. In addition, MMP10 induces Ca²⁺ mobilization in DRG neurons but through a PAR1-independent mechanism. These findings uncover a previously unrecognized role for MMP signaling in sensory neurons, highlighting a potential mechanism by which MMPs could contribute to the pronociceptive environment in the inflamed bowel.<b>NEW & NOTEWORTHY</b> Matrix metalloproteases-elevated in colonic biopsies from patients with Crohn's disease-stimulate a subset of nociceptive sensory neurons. As such, matrix metalloproteases may contribute to the pronociceptive environment in the inflamed bowel.