CCR2-dependent monocytes gut-homing contributes to enteric neuroplastic changes in a mouse model of diet-induced obesity
Abstract
Background Enteric inflammation and immune cell activation promote enteric neuroplastic changes and CCR2dependent monocyte recruitment, contributing to obesity-associated colonic dysmotility and chronic inflammation. Here, we examined the role of C-C motif chemokine ligand (CCL2)/C-C chemokine receptor 2 (CCR2)-mediated blood monocytes gut-homing in colonic motor dysfunctions in mice with high fat diet (HFD)-induced obesity.Methods Wild-type C57BL/6J mice were fed HFD or standard diet (SD) for 8 weeks. Subgroups received the CCR2 antagonist RS504393 (2 mg/kg/day, oral) or vehicle throughout the HFD intake. Body weight and body mass index (BMI) were monitored starting from HFD intake. Colonic transit was assessed by fecal pellet output. In vitro colonic contractility was evaluated by assessing substance P (SP)-induced contractile responses, along with analysis of SP-positive neurons. Immunohistochemistry was used to quantify CCR2⁺ monocytes and CD64⁺/Iba-1⁺ macrophages within the myenteric plexus. Colonic expression of CCL2 in enteric neurons (HuC/D⁺) and glial cells (GFAP⁺) was assessed. Gut vascular barrier integrity was evaluated via PV-1 expression and plasma lipopolysaccharide-binding protein (LBP) levels. The effects of CCR2 blockade on motility, neuronal SP expression, chemokine expression, and monocyte recruitment were analyzed.
Results HFD mice displayed an increase in body weight and BMI. An altered in vivo colonic transit along with an increased in vitro tachykininergic contractions and myenteric SP immunopositivity were detected in HFD mice. HFD mice exhibited marked infiltration of monocyte-derived macrophages (CD64⁺, Iba-1⁺) within the muscularis layer, in close spatial association with SP-positive nerve fibers and neuromuscular vasculature. Increased CCL2 expression was observed in both enteric neurons and glial cells, alongside evidence of compromised gut vascular barrier function. Pharmacological CCR2 inhibition attenuated weight gain and significantly improved colonic transit. Moreover, CCR2 blockade normalized tachykininergic hyperactivity, reduced SP expression, decreased colonic CCL2 levels, and limited monocyte/macrophage accumulation in the enteric neuromuscular compartment.
ConclusionDuring obesity, the activation of the CCL2/CCR2 pathway promotes the recruitment of blood-derived monocytes to the gut, driving neuroimmune remodelling within the enteric nervous system. Blood monocytederived macrophages modulate tachykininergic pathways, contributing to colonic dysmotility. Targeting CCR2dependent gut immune cell trafficking may represent a novel therapeutic strategy for obesity-associated GI dysfunction.
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BibTeX
@article{pierucci2026ccr2dependent,
title = {{CCR2-dependent monocytes gut-homing contributes to enteric neuroplastic changes in a mouse model of diet-induced obesity}},
author = {Clarissa Pierucci and Sofia Faggin and Laura Benvenuti and Valentina Caputi and Chiara Ippolito and Cristina Segnani and Vanessa D’antongiovanni and Giulia Valdiserra and Lorenzo Flori and Rocchina Colucci and Maria Cecilia Giron and Luca Antonioli and Nunzia Bernardini and Carolina Pellegrini},
journal = {Molecular Medicine},
year = {2026},
month = jul,
doi = {10.1186/s10020-026-01560-y},
url = {https://hal.inrae.fr/hal-05806055v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - CCR2-dependent monocytes gut-homing contributes to enteric neuroplastic changes in a mouse model of diet-induced obesity
AU - Clarissa Pierucci
AU - Sofia Faggin
AU - Laura Benvenuti
AU - Valentina Caputi
AU - Chiara Ippolito
AU - Cristina Segnani
AU - Vanessa D’antongiovanni
AU - Giulia Valdiserra
AU - Lorenzo Flori
AU - Rocchina Colucci
AU - Maria Cecilia Giron
AU - Luca Antonioli
AU - Nunzia Bernardini
AU - Carolina Pellegrini
PY - 2026
DA - 2026/07/15
JO - Molecular Medicine
DO - 10.1186/s10020-026-01560-y
UR - https://hal.inrae.fr/hal-05806055v1
AB - Background Enteric inflammation and immune cell activation promote enteric neuroplastic changes and CCR2dependent monocyte recruitment, contributing to obesity-associated colonic dysmotility and chronic inflammation. Here, we examined the role of C-C motif chemokine ligand (CCL2)/C-C chemokine receptor 2 (CCR2)-mediated blood monocytes gut-homing in colonic motor dysfunctions in mice with high fat diet (HFD)-induced obesity.Methods Wild-type C57BL/6J mice were fed HFD or standard diet (SD) for 8 weeks. Subgroups received the CCR2 antagonist RS504393 (2 mg/kg/day, oral) or vehicle throughout the HFD intake. Body weight and body mass index (BMI) were monitored starting from HFD intake. Colonic transit was assessed by fecal pellet output. In vitro colonic contractility was evaluated by assessing substance P (SP)-induced contractile responses, along with analysis of SP-positive neurons. Immunohistochemistry was used to quantify CCR2⁺ monocytes and CD64⁺/Iba-1⁺ macrophages within the myenteric plexus. Colonic expression of CCL2 in enteric neurons (HuC/D⁺) and glial cells (GFAP⁺) was assessed. Gut vascular barrier integrity was evaluated via PV-1 expression and plasma lipopolysaccharide-binding protein (LBP) levels. The effects of CCR2 blockade on motility, neuronal SP expression, chemokine expression, and monocyte recruitment were analyzed. Results HFD mice displayed an increase in body weight and BMI. An altered in vivo colonic transit along with an increased in vitro tachykininergic contractions and myenteric SP immunopositivity were detected in HFD mice. HFD mice exhibited marked infiltration of monocyte-derived macrophages (CD64⁺, Iba-1⁺) within the muscularis layer, in close spatial association with SP-positive nerve fibers and neuromuscular vasculature. Increased CCL2 expression was observed in both enteric neurons and glial cells, alongside evidence of compromised gut vascular barrier function. Pharmacological CCR2 inhibition attenuated weight gain and significantly improved colonic transit. Moreover, CCR2 blockade normalized tachykininergic hyperactivity, reduced SP expression, decreased colonic CCL2 levels, and limited monocyte/macrophage accumulation in the enteric neuromuscular compartment. ConclusionDuring obesity, the activation of the CCL2/CCR2 pathway promotes the recruitment of blood-derived monocytes to the gut, driving neuroimmune remodelling within the enteric nervous system. Blood monocytederived macrophages modulate tachykininergic pathways, contributing to colonic dysmotility. Targeting CCR2dependent gut immune cell trafficking may represent a novel therapeutic strategy for obesity-associated GI dysfunction.
SN - 1076-1551
SN - 1528-3658
ER -