Transient Receptor Potential Melastatin 8 Plays a Key Role in Dextran Sulfate Sodium-Induced Murine Colitis via...

Transient receptor potential melastatin 8 (TRPM8) is a cold-sensitive Ca²⁺-permeable ion channel that regulates intestinal inflammation. This study was aimed to elucidate the role of TRPM8 in enteric macrophages and spinal afferent sensory neurons during dextran sulfate sodium (DSS)-induced colitis.

The role of TRPM8 in the progression of colonic inflammation was examined in 2% DSS-induced colitis by immunohistochemistry, reverse transcription-polymerase chain reaction, visceral sensing assessment, and flow cytometry. The role of TRPM8 in sensory neurons and macrophages was investigated using primary cultured dorsal root ganglion (DRG) neurons and bone marrow-derived macrophages (BMDMs).

DSS-induced colitis was significantly aggravated in TRPM8-deficient (KO) mice compared with that in wild-type (WT) mice. In the colitis model, KO mice showed lower IL-10 mRNA levels than WT mice, but IL-6, IL-1β, and TNF-α levels were not affected. TRPM8 expression was upregulated in the distal colon and DRG following DSS administration. In the distal colon, TRPM8-immunoreactive cells and nerve fibers colocalized with F4/80 and substance P/calcitonin gene-related peptide (CGRP), respectively. In the DRG, TRPM8 neuron subtypes were labeled by neurofilament 200, substance P, CGRP, and tyrosine kinase receptor A. In cultured DRG neurons, TRPM8 deficiency attenuated lipopolysaccharide (LPS)-elicited CGRP release but did not affect substance P release. In BMDMs, TRPM8 deficiency significantly decreased LPS- and LPS/CGRP-elicited upregulation of IL-10 mRNA compared with that in WT animals.

TRPM8 protects against DSS-induced experimental colitis via regulating CGRP release from sensory neurons and IL-10 production in enteric macrophages during intestinal inflammation.