ADP/P2Y1 aggravates inflammatory bowel disease through ERK5-mediated NLRP3 inflammasome activation |
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| Institution: | 1. Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, 200241, China;2. Department of Pathology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 211166, China;3. Joint Center for Translational Medicine, Fengxian District Central Hospital, No. 6600 Nanfeng Road, Fengxian District, Shanghai, 201499, China;4. Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, TX, 77030, USA;1. Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, 200241, China;2. Department of Pathology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 211166, China;3. Joint Center for Translational Medicine, Fengxian District Central Hospital, No. 6600 Nanfeng Road, Fengxian District, Shanghai, 201499, China;4. Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, TX, 77030, USA |
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| 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. |
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