Dietary targeting of TRPM8 rewires macrophage immunometabolism reducing colitis severity

The interplay between diet, host genetics, microbiota, and immune system has a key role in the pathogenesis of inflammatory bowel disease (IBD). Although the causal pathophysiological mechanisms remain unknown, numerous dietary nutrients have been shown to regulate gut mucosal immune function, being effective in influencing innate or adaptive immunity. Here, we proved that transient receptor potential melastatin 8 (TRPM8), a non-selective cation channel, mediates LPS- evoked Ca<sup>2+</sup> influx in macrophages leading to their activation. Additionally, we showed that TRPM8 is selectively blocked by the dietary flavonoid luteolin, which induced a pro-tolerogenic phenotype in pro-inflammatory macrophages. Accordingly, genetic deletion of Trpm8 in macrophages caused a deficit in the activation of pro-inflammatory metabolic and transcriptional reprogramming, leading to reduced production of key pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. The TRPM8 anti-inflammatory effect was found to be dependent on lactate which in turn induces IL-10 gene expression. Adoptive transfer of TRPM8-deficient bone marrow in wild-type mice improved intestinal inflammation in a model of colitis. Accordingly, oral administration of luteolin protected mice against colitis through an impairment in the innate immune response. Our study reveals the potential of targeting TRPM8 through specific nutrient interventions to regulate immune function in sub-clinical scenarios or to treat inflammatory diseases, primarily driven by chronic immune responses, such as IBD.

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Publication Details

Journal
Cell Death and Disease
Published
2025-04-25
DOI
https://doi.org/10.1038/s41419-025-07553-9
Citations
6
Primary Topic
Ion Channels and Receptors
Type
article
Field-Weighted Citation Impact
8.79

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article

Dietary targeting of TRPM8 rewires macrophage immunometabolism reducing colitis severity

Lisa Zanoletti, María Cruz Miraglia, Donatella Cicia, Karel Talavera et al.
6 citations
Cell Death and Disease
Ion Channels and Receptors
8.79
article

Dietary targeting of TRPM8 rewires macrophage immunometabolism reducing colitis severity

Lisa Zanoletti, María Cruz Miraglia, Donatella Cicia, Karel Talavera, Aniello Schiano Moriello, M F Nanì, Nunzia Iaccarino, P De Cicco, Gianluca Matteoli, Fabio Arturo Iannotti, Bo-Jun Ke, Ester Pagano, Raffaele Capasso, Annalisa Chiavaroli, Claudio Ferrante, Antonio Randazzo, Lies van Baarle, Francesca Biscu, Angelo A. Izzo, Ilaria Elia, Silvia Cadenas de Miguel
article en
6 citations

Abstract

The interplay between diet, host genetics, microbiota, and immune system has a key role in the pathogenesis of inflammatory bowel disease (IBD). Although the causal pathophysiological mechanisms remain unknown, numerous dietary nutrients have been shown to regulate gut mucosal immune function, being effective in influencing innate or adaptive immunity. Here, we proved that transient receptor potential melastatin 8 (TRPM8), a non-selective cation channel, mediates LPS- evoked Ca<sup>2+</sup> influx in macrophages leading to their activation. Additionally, we showed that TRPM8 is selectively blocked by the dietary flavonoid luteolin, which induced a pro-tolerogenic phenotype in pro-inflammatory macrophages. Accordingly, genetic deletion of Trpm8 in macrophages caused a deficit in the activation of pro-inflammatory metabolic and transcriptional reprogramming, leading to reduced production of key pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. The TRPM8 anti-inflammatory effect was found to be dependent on lactate which in turn induces IL-10 gene expression. Adoptive transfer of TRPM8-deficient bone marrow in wild-type mice improved intestinal inflammation in a model of colitis. Accordingly, oral administration of luteolin protected mice against colitis through an impairment in the innate immune response. Our study reveals the potential of targeting TRPM8 through specific nutrient interventions to regulate immune function in sub-clinical scenarios or to treat inflammatory diseases, primarily driven by chronic immune responses, such as IBD.

Cell Death and DiseaseVol. 16(1)
University of Pavia (IT), University of Chieti-Pescara (IT), Federico II University Hospital (IT), Istituto di Chimica Biomolecolare (IT), Centre for Inflammation Research (GB), VIB-KU Leuven Center for Brain & Disease Research (BE), University of Naples Federico II (IT), University of Edinburgh (GB), KU Leuven (BE)
Università degli Studi di Napoli Federico II, European Commission, Fonds Wetenschappelijk Onderzoek, Ministero dell’Istruzione, dell’Università e della Ricerca, KU Leuven, Ministero dell'Università e della Ricerca
Good health and well-being
Openalex Percentile: Top 2%
Ion Channels and Receptors
8.79
DOIOpen Access PDFOpenAlex
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