Electroacupuncture relieves joint pain by weakening the enhanced neuronal CXCR2-TRPA1 signaling in peripheral sensory neurons of a mouse model of acute gouty arthritis.

Abstract

<p>BACKGROUND: Electroacupuncture (EA) relieves acute gouty arthritis (AGA), but its mechanisms are poorly understood. Our recent work reveals that CXCR2-TRPA1 coupling in dorsal root ganglion (DRG) neurons mediates joint pain and facilitates inflammation in AGA model animals via promoting sensory neuron excitability and neutrophil infiltration. We hereby explored whether EA alleviates AGA via modulating CXCR2-TRPA1 signaling in DRG neurons. METHODS: AGA model was established in mice by injecting monosodium urate to ankle joints. EA was applied on bilateral ST36 acupoints. Biochemical assays, RNA-Sequencing, behavioral tests and Ca2+ imaging, etc. were used for mechanism exploration. RESULTS: EA improves AGA in model mice. EA reduced CXCR2 overexpression in joint innervating DRG neurons of model mice by reducing STAT3 overactivation. Neuronal CXCR2-TRPA1 coupling underwent enhancement during AGA, which was weakened by EA. Targeted knockdown of CXCR2 expression via AAV-PHP.S capsid in joint innervating DRG neurons ameliorated AGA in model mice, an effect mimicking EA. EA further reduced downstream effects conveyed through neuronal CXCR2-TRPA1 signaling, including CGRP/substance P release and neutrophil infiltration, in ankle joints of model mice. Conversely, targeted overexpression of CXCR2 in DRG neurons abrogated the ameliorative effects of EA. CONCLUSIONS: Our study demonstrates that EA reduces STAT3 activation to restrain CXCR2 overexpression in DRG during AGA. This effect further attenuates the enhanced neuronal CXCR2-TRPA1 coupling in DRG neurons, resulting in less sensory neuron activation, neuropeptide release and neurogenic inflammation. Collectively, this work provides novel insights into how EA ameliorates AGA, thereby further supporting EA as a viable treatment option for AGA.</p>