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ADP/P2Y1 aggravates inflammatory bowel disease through ERK5-mediated NLRP3 inflammasome activation
Chengfei Zhang1,2, Juliang Qin1,3, Su Zhang1
1Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, 200241, China.
Abstract:
Inflammasomes are essential for inflammation and pathogen elimination in response to microbial infection and endogenous danger signals. However, the mechanism of inflammasome activation by endogenous danger signals mediated posttranslational modification and the connection between inflammasomes and inflammatory diseases remains elusive. In this study, we found that ADP was highly released from injured colonic tissue as a danger signal during inflammatory bowel disease. Consequently, extracellular ADP activated the NLRP3 inflammasome through P2Y1 receptor-mediated calcium signaling, which led to the maturation and secretion of IL-1β and further aggravation of experimental colitis. Genetic ablation or pharmacological blockade of the P2Y1 receptor significantly ameliorated DSS-induced colitis and endotoxic shock through reducing NLRP3 inflammasome activation. Moreover, ERK5-mediated tyrosine phosphorylation of ASC was essential for activation of the NLRP3 inflammasome. Thus, our study provides a novel theoretical basis for posttranslational modification of ASC in NLRP3 inflammasome activation and revealed that ADP/P2Y1 is a potential drug target for inflammatory bowel disease.
Insights
Extracellular adenosine diphosphate (ADP) acts as a danger signal, activating the NLRP3 inflammasome and worsening inflammatory bowel disease. Blocking the P2Y1 receptor reduces this activation, offering a potential therapeutic target for colitis.
Area of Science:
- Immunology
- Molecular Biology
- Gastroenterology
Background:
- Inflammasomes are crucial for immune responses to pathogens and danger signals.
- The precise mechanisms linking inflammasomes to inflammatory diseases, particularly via endogenous danger signals and posttranslational modifications, require further elucidation.
Purpose of the Study:
- To investigate the role of extracellular adenosine diphosphate (ADP) as an endogenous danger signal in inflammatory bowel disease (IBD).
- To elucidate the mechanism by which ADP activates the NLRP3 inflammasome and exacerbates experimental colitis.
- To identify potential therapeutic targets for IBD based on inflammasome activation pathways.
Main Methods:
- Measurement of ADP release from injured colonic tissue.
- Analysis of NLRP3 inflammasome activation in response to extracellular ADP.
- Utilizing genetic ablation and pharmacological blockade of the P2Y1 receptor.
- Investigating the role of ERK5-mediated tyrosine phosphorylation of ASC in inflammasome activation.
Main Results:
- High levels of ADP were detected in injured colonic tissue during inflammatory bowel disease.
- Extracellular ADP activates the NLRP3 inflammasome via P2Y1 receptor-mediated calcium signaling, leading to IL-1β maturation and secretion.
- Genetic or pharmacological inhibition of P2Y1 receptor significantly ameliorated DSS-induced colitis and endotoxic shock by suppressing NLRP3 inflammasome activation.
- ERK5-mediated tyrosine phosphorylation of ASC is critical for NLRP3 inflammasome activation.
Conclusions:
- ADP serves as a key endogenous danger signal in IBD, activating the NLRP3 inflammasome through the P2Y1 receptor.
- The ADP/P2Y1 axis contributes to the pathogenesis of experimental colitis and endotoxic shock.
- Targeting the P2Y1 receptor offers a promising therapeutic strategy for inflammatory bowel disease.
- Posttranslational modification of ASC, specifically ERK5-mediated tyrosine phosphorylation, is essential for NLRP3 inflammasome activation.
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