TRPM8 deficiency aggravates DSS-induced colitis by impairing CGRP release and IL-10 production

Inflammatory bowel disease (IBD), particularly colitis, involves complex immune responses and often lacks effective long-term treatments. Intestinal inflammation is regulated by various factors, including ion channels. Transient receptor potential melastatin 8 (TRPM8) is a cold-sensitive Ca2+-permeable ion channel known to influence intestinal inflammation. However, its specific role in modulating enteric macrophages and spinal afferent sensory neurons during dextran sulfate sodium (DSS)-induced colitis remained unclear, representing a critical gap in understanding disease progression and potential therapeutic targets.

Researchers investigated TRPM8's role in dextran sulfate sodium (DSS)-induced colitis using TRPM8-deficient (KO) and wild-type (WT) mice. Colitis was induced with 2% DSS. They assessed inflammation via immunohistochemistry, reverse transcription-polymerase chain reaction (RT-qPCR), visceral sensing assessment, and flow cytometry. Further mechanistic studies used primary cultured dorsal root ganglion (DRG) neurons and bone marrow-derived macrophages (BMDMs) to evaluate lipopolysaccharide (LPS)-elicited responses and calcitonin gene-related peptide (CGRP) interactions.

DSS-induced colitis was significantly aggravated in TRPM8-deficient (KO) mice compared to wild-type (WT) mice. In the colitis model, KO mice exhibited lower IL-10 mRNA levels than WT mice, while IL-6, IL-1β, and TNF-α levels remained unaffected. TRPM8 expression was upregulated in the distal colon and DRG following DSS administration. In the distal colon, TRPM8-immunoreactive cells colocalized with F4/80 (macrophages), and nerve fibers with substance P and calcitonin gene-related peptide (CGRP). 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 LPS-elicited CGRP release but did not affect substance P release. Furthermore, in BMDMs, TRPM8 deficiency significantly decreased LPS- and LPS/CGRP-elicited upregulation of IL-10 mRNA compared to WT animals, highlighting a critical role in macrophage secretory activities.