Dual function of MrgprB2 receptor-dependent neural immune axis in chronic pain

Neuro-immune interactions have been recognized to be involved in the development of neuropathic pain induced by chemotherapeutic drugs (CINP). However, its role in pain resolution remains largely unknown, particularly concerning mast cells. To investigate the bidirectional modulation of mast cell Mas-related G protein-coupled receptor B2 (MrgprB2)-mediated neuro-immune interactions in CINP. CINP model was established in wild-type mice, Mas-related G protein-coupled receptor D knockout (MrgprD-/-) mice, mast cell-deficient mice, MrgprB2 knockout (MrgprB2-/-) mice, and MrgprB2-Cre tdTomato mice. The role of MrgprB2 receptor in CINP was investigated by calcium imaging, cytokine antibody arrays, mining of single-cell sequencing databases, immunofluorescence, western blotting, co-immunoprecipitation (Co-IP), among other methodologies. We observed that cisplatin-induced allodynia was significantly inhibited in MrgprB2-/- mice, which was attributed to the blockade of tryptase release and the suppression of upregulation of protease-activated receptor 2 (PAR2) expression in dorsal root ganglion (DRG). Thus, the activation of MrgprB2/Tryptase/PAR2 axis contributed to the development of cisplatin-induced pain. In addition, we also found that there was co-expression of PAR2 and MrgprD in DRG neurons. And activation of PAR2 can negatively regulate the expression of MrgprD, whether in a physiological state or in a chronic pain condition. Consequently, MrgprD expression was down-regulated by the activation of the MrgprB2/Tryptase/PAR2 axis during the later stages of CINP, which was associated with pain relief. Therefore, the activation of MrgprB2/Tryptase/PAR2 axis also contributed to the alleviation of cisplatin-induced pain. This finding was in line with the phenomenon that persistent stimulation by cisplatin did not cause a continuous increase in pain. Our research elucidated the bidirectional modulation of MrgprB2-dependent neural immune axis in CINP. This study emphasized that MrgprB2 is a critical target for early intervention in CINP, and highlighted the necessity of considering the mechanism differences at different stages in pain management.