Mast cell–expressed Mrgprb2/MRGPRX2 mediates gout pain and inflammation via a neuroimmune axis
Lin Yang, Chengxi Liu, Jin Xiao, Yu Song, Huan Chen, Dan Li, Cong Zou, Tao Hong, Yinglan Liu, Dake Qi, Nathachit Limjunyawong, Wenjie Liu, Lintao Qu
Lin Yang, Chengxi Liu, Jin Xiao, Yu Song, Huan Chen, Dan Li, Cong Zou, Tao Hong, Yinglan Liu, Dake Qi, Nathachit Limjunyawong, Wenjie Liu, Lintao Qu
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Research Article Immunology Neuroscience

Mast cell–expressed Mrgprb2/MRGPRX2 mediates gout pain and inflammation via a neuroimmune axis

Abstract

Acute severe joint pain is a major symptom in gouty arthritis (GA), and its adequate treatment represents an unmet medical need. Mrgprb2, a specific mast cell receptor, has been implicated in the generation of chronic pain by mobilizing mast cell degranulation, yet its significance in GA pain and joint inflammation is still not well defined. Here, we found that Mrgprb2 was expressed in mouse synovial mast cells. In a murine model of GA, acute blockade or genetic deletion of Mrgprb2 significantly attenuated arthritis pain and hyperexcitability of joint nociceptors with significant reductions in innate immune cell recruitment in the synovium. Under naive conditions, activation of synovial Mrgprb2 was sufficient to excite peripheral terminals of joint nociceptors to induce acute joint hypernociception via the mobilization of mast cell degranulation. Additionally, the level of the neuropeptide substance P (SP) was elevated in the synovium of GA model mice. Using humanized MRGPRX2-knockin mice, we revealed that SP contributed to joint pain and inflammation by activating mast cells through Mrgprb2/MRGPRX2. These findings suggest that synovial mast cell–expressed Mrgprb2/MRGPRX2 merits consideration as a key neuroimmune player and a potential therapeutic target for treating GA pain and joint inflammation.

Authors

Lin Yang, Chengxi Liu, Jin Xiao, Yu Song, Huan Chen, Dan Li, Cong Zou, Tao Hong, Yinglan Liu, Dake Qi, Nathachit Limjunyawong, Wenjie Liu, Lintao Qu

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Figure 5

Activation of synovial Mrgprb2 by C48/80 evokes behavioral signs of joint hypernociception.

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Activation of synovial Mrgprb2 by C48/80 evokes behavioral signs of join...
(A) Schematic illustration of intra-articular (i.a.) administration protocol of C48/80 (1.5 μg, 10 μL). Pain-related behaviors were assessed within 2 hours after injection. Figure created in BioRender (Qu L, 2026, https://BioRender.com/snnmb6q). (B–E) Changes of mechanical threshold in the ankle (B), paw withdrawal frequency (PWF) responding to 0.07g force in the hind paw (C), paw withdrawal latency (PWL) to radiant heat in the hind paw (D), and joint diameter (E) following i.a. injection of C48/80 in Mrgprb2+/+ (n = 10) and Mrgprb2–/– (n = 9) mice. *P < 0.05 vs. baseline (BL); #P < 0.05, ##P < 0.01 vs. Mrgprb2+/+; 2-way ANOVA (repeated measures) followed by Bonferroni’s correction. (F) Generation of Mrgprb2Cre DTA mouse line. Figure created in BioRender (Qu L, 2026, https://BioRender.com/t0h8dej). (G) Representative IHC images of knee joint sections stained for c-Kit (green) in Mrgprb2Cre+;DTA and Cre– littermates. Red arrows show c-Kit+ cells. S, synovium. Scale bar: 200 μm. (H) Quantification showed a loss of MCs in the synovium of Mrgprb2Cre+;DTA mice but not Cre– littermate controls. n = 4 mice per group; **P < 0.01 vs. Mrgprb2Cre+;DTA; unpaired 2-tailed Student’s t test. (I–L) Mrgprb2Cre+;DTA mice exhibited higher mechanical threshold in the ankle (I), lower PWF in response to 0.07g force (J), longer PWL in the hind paw (K), and smaller ankle diameter (L) following i.a. injection of C48/80 compared with Cre– littermates. *P < 0.05 vs. BL; #P < 0.05 vs. Mrgprb2Cre– DTA; 2-way ANOVA (repeated measures) followed by Bonferroni’s correction. (M) Representative flow cytometric profiles of MRGPRX2 expression (CD45+c-Kit+MRGPRX2+) in WT and MRGPRX2-knockout LAD2 (MRGPRX2-KO-LAD2) cells. (N) Quantification showed loss of MRGPRX2 expression in MRGPRX2-KO-LAD2 cells compared with WT controls. n = 6 biological repeats per group; *P < 0.001 vs. WT; unpaired 2-tailed Student’s t test. (O) C48/80- and C3a-induced β-hexosaminidase (β-hex) release in WT and MRGPRX2-KO-LAD2 cells. n = 8 biological repeats per group; ***P < 0.001 vs. Veh; ###P < 0.001 vs. WT-LAD2 cells; 2-way ANOVA (repeated measures) followed by Bonferroni’s correction.