Neuroimmune activation of the TRPV1–RAMP1 axis drives type 2 immunity to repair intestinal barrier and alleviate metabolic disease

Abstract

Introduction Obesity is closely associated with intestinal barrier dysfunction and chronic inflammation. Group 2 innate lymphoid cells (ILC2s) can receive and integrate signals from neuropeptides, neurotransmitters, and epithelial cells, thereby regulating local tissue inflammatory responses and promoting repair. However, the specific mechanism by which the nociceptor Transient Receptor Potential Vanilloid 1 (TRPV1) interacts with ILC2s to regulate intestinal homeostasis in obesity remains unclear. Objective This study aimed to investigate whether electroacupuncture (EA) ameliorated obesity-mediated intestinal injury by modulating type 2 immune responses via the TRPV1- calcitonin gene-related peptide (CGRP)- receptor activity-modifying protein 1 (RAMP1) axis. Methods A high-fat diet-induced obese mouse model was employed. The expression levels of TRPV1 and CGRP, the abundance of ILC2s, and the levels of type 2 cytokines IL-5 and IL-13 in colon tissues were assessed using flow cytometry, immunofluorescence staining, and Western blotting. Intestinal pathological changes and goblet cell status were evaluated via hematoxylin and eosin staining and Alcian blue-periodic acid-Schiff staining. Mechanistic verification was performed by specific ablation of TRPV1+ dorsal root ganglion neurons and pharmacological inhibition of the CGRP receptor or RAMP1. Results EA treatment significantly increased CGRP derived from TRPV1-expressing sensory neurons, which subsequently activated type 2 immunity, as evidenced by the expansion of ILC2s and upregulation of related cytokines. This immune activation ultimately promoted the differentiation and proliferation of goblet cells and ameliorated high-fat diet-induced intestinal barrier damage. Notably, in mice with specific ablation of TRPV1+ dorsal root ganglion neurons, or treatment with a CGRP receptor antagonist, or ablation of intestinal ILC2s, EA failed to induce intestinal type 2 immune activation or alleviate diet-induced intestinal injury. Conclusion Our findings demonstrate that electroacupuncture activates intestinal type 2 immunity via the TRPV1-CGRP-RAMP1 axis, identifying this pathway as a crucial mechanism for repairing obesity-associated intestinal barrier dysfunction.