An interorgan neuroimmune circuit promotes visceral hypersensitivity

Visceral pain disorders such as interstitial cystitis/bladder pain syndrome (IC/BPS) and irritable bowel syndrome (IBS) often manifest concurrently in the bladder and colon. Yet, the mechanistic basis of such comorbidities and the transmission of neural hypersensitivity across organ systems has remained a mystery. Here, we identify a mast cell-sensory neuron circuit that initiates bladder inflammation and simultaneously propagates neural hypersensitivity to the colon in a murine model of IC/BPS. We unveil anatomic heterogeneity of mast cells in relation to nociceptors in the bladder and their critical dependence on Mas-related G protein-coupled receptor B2 (MrgprB2) to promote visceral hypersensitivity. Employing retrograde neuronal tracing, in vivo calcium imaging, and intersectional genetics, we uncover a population of polyorganic sensory neurons that simultaneously innervate multiple organs and exhibit functional convergence. Importantly, using humanized mice, we demonstrate that pharmacological blockade of mast cell-expressed MRGPRX2, the human ortholog of MrgprB2, attenuates both bladder pathology and colonic hypersensitivity. Our studies reveal evolutionarily conserved neuroimmune mechanisms by which immune cells can directly convey signals from one organ to another through sensory neurons, in the absence of physical proximity, representing a new therapeutic paradigm.