P2X7 receptor contributes to hepatic inflammation and collagen deposition in methionine- and choline-deficient diet-fed mice
5 affiliations
- 1Laboratory of Immunophysiology, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro
- 2Center for Technological Development in Health, Oswaldo Cruz Foundation
- 3Laboratory of Neuroimmunology, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro
- 4Laboratory of Biochemistry of Lipids and Lipoproteins, Leopoldo de Meis Institute of Medical Biochemistry, Federal University of Rio de Janeiro
- 5Laboratory of Immunopathology, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro
Abstract
Introduction: Metabolic-Dysfunction-Associated Steatohepatitis (MASH) is characterized by hepatic steatosis, inflammation, and progressive liver injury, with growing evidence implicating purinergic signaling and inflammasome activation in disease progression. Here, we investigated the role of the P2X7 receptor and caspase-1/11 signaling in methionine- and choline-deficient (MCD) diet-induced liver injury in mice.
Methods: Mice were fed an MCD diet to induce liver injury, and hepatic steatosis, inflammation, and tissue injury were assessed by histopathological analysis. Hepatic triacylglycerol and cholesterol accumulation, Il1b mRNA expression, and IL-1β protein levels were evaluated. The hepatic expression profile of purinergic receptors, including P2Y ₁ , P2Y ₄ , P2Y ₆ , P2Y ₁₂ , and P2Y ₁₄ , was also investigated in wild-type and P2X7- and/or caspase-1/11-deficient mice.
Results: MCD diet feeding induced significant weight loss and marked histopathological alterations, including hepatic steatosis, inflammatory infiltrates, and hepatocellular injury, accompanied by increased hepatic triacylglycerol and cholesterol accumulation. Hepatic injury was partially dependent on caspase-1/11 signaling, whereas hepatic inflammation was partially dependent on the P2X7 receptor. Although Il1b mRNA expression increased following MCD diet feeding, this increase was significant only in wild-type mice, whereas increased IL-1β protein levels were observed only in wild-type animals, suggesting that P2X7 receptor signaling and caspase-1/11 may contribute to IL-1β maturation during MCD diet-induced liver injury. In addition, MCD diet feeding promoted marked remodeling of the hepatic purinergic profile, characterized by downregulation of P2Y ₁ and P2Y ₄ receptors and genotype-dependent regulation of P2Y ₁₂ , whereas P2Y ₆ and P2Y ₁₄ expression remained largely unchanged.
Discussion: Together, these findings demonstrate that the P2X7 receptor and caspase-1/11 play a role in amplifying inflammatory responses and reshaping the hepatic purinergic microenvironment during steatohepatitis progression, highlighting the P2X7 receptor as a potential therapeutic target in chronic liver disease.
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BibTeX
@article{silva2026p2x7,
title = {{P2X7 receptor contributes to hepatic inflammation and collagen deposition in methionine- and choline-deficient diet-fed mice}},
author = {Sthefani Rodrigues Batista da Silva and Fabiana Cristina-Rodrigues and Mariana M. Chaves and Isabele Pinheiro Cruz and Lorraine de Oliveira da Cruz and Maria Fernanda Carvalho de Araujo and Soraia das Neves Vieira Cavalcanti and Georgia Correa Atella and Christina Maeda Takiya and Luiz Eduardo Baggio Savio and Robson Coutinho-Silva},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1909005},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1909005/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - P2X7 receptor contributes to hepatic inflammation and collagen deposition in methionine- and choline-deficient diet-fed mice
AU - Sthefani Rodrigues Batista da Silva
AU - Fabiana Cristina-Rodrigues
AU - Mariana M. Chaves
AU - Isabele Pinheiro Cruz
AU - Lorraine de Oliveira da Cruz
AU - Maria Fernanda Carvalho de Araujo
AU - Soraia das Neves Vieira Cavalcanti
AU - Georgia Correa Atella
AU - Christina Maeda Takiya
AU - Luiz Eduardo Baggio Savio
AU - Robson Coutinho-Silva
PY - 2026
DA - 2026/10/07
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1909005
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1909005/full
AB - Introduction: Metabolic-Dysfunction-Associated Steatohepatitis (MASH) is characterized by hepatic steatosis, inflammation, and progressive liver injury, with growing evidence implicating purinergic signaling and inflammasome activation in disease progression. Here, we investigated the role of the P2X7 receptor and caspase-1/11 signaling in methionine- and choline-deficient (MCD) diet-induced liver injury in mice. Methods: Mice were fed an MCD diet to induce liver injury, and hepatic steatosis, inflammation, and tissue injury were assessed by histopathological analysis. Hepatic triacylglycerol and cholesterol accumulation, Il1b mRNA expression, and IL-1β protein levels were evaluated. The hepatic expression profile of purinergic receptors, including P2Y ₁ , P2Y ₄ , P2Y ₆ , P2Y ₁₂ , and P2Y ₁₄ , was also investigated in wild-type and P2X7- and/or caspase-1/11-deficient mice. Results: MCD diet feeding induced significant weight loss and marked histopathological alterations, including hepatic steatosis, inflammatory infiltrates, and hepatocellular injury, accompanied by increased hepatic triacylglycerol and cholesterol accumulation. Hepatic injury was partially dependent on caspase-1/11 signaling, whereas hepatic inflammation was partially dependent on the P2X7 receptor. Although Il1b mRNA expression increased following MCD diet feeding, this increase was significant only in wild-type mice, whereas increased IL-1β protein levels were observed only in wild-type animals, suggesting that P2X7 receptor signaling and caspase-1/11 may contribute to IL-1β maturation during MCD diet-induced liver injury. In addition, MCD diet feeding promoted marked remodeling of the hepatic purinergic profile, characterized by downregulation of P2Y ₁ and P2Y ₄ receptors and genotype-dependent regulation of P2Y ₁₂ , whereas P2Y ₆ and P2Y ₁₄ expression remained largely unchanged. Discussion: Together, these findings demonstrate that the P2X7 receptor and caspase-1/11 play a role in amplifying inflammatory responses and reshaping the hepatic purinergic microenvironment during steatohepatitis progression, highlighting the P2X7 receptor as a potential therapeutic target in chronic liver disease.
SN - 1663-9812
ER -