ADP/P2Y1 aggravates inflammatory bowel disease through ERK5-mediated NLRP3 inflammasome activation

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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Fig. 1: ADP is a danger signal that aggravates DSS-induced colitis.
Fig. 2: ADP facilitated colon production of IL-1β.
Fig. 3: ADP facilitated the production of IL-1β through activating the NLRP3 inflammasome.
Fig. 4: ADP activates the NLRP3 inflammasome through P2Y1 and the calcium pathway.
Fig. 5: P2Y1 deficiency attenuates DSS-induced colitis.
Fig. 6: ERK5 is essential for ADP to activate the NLRP3 inflammasome.
Fig. 7: ERK5 interacts with NLRP3/ASC and regulates ASC phosphorylation.

Data availability

All data that support the findings of this study are available from the corresponding authors upon request.

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Acknowledgements

This work was supported by National Key R&D Program of China [2018YFA0507001 to B.D.]; National Natural Science Foundation of China [31770969 to B.D., 81672811 and 81871250 to M.Q., and 81830083 to M.L., 81902892 to J.Q.]; Innovation Program of Shanghai Municipal Education Commission [2017-01-07-00-05-E00011 to M.L.]; and Natural Science Foundation of Jiangsu Province [Grant no. BK20190657 to C.Z.].

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B.D., M.Q., and M.L. supervised the project. B.D. and C.Z. conceived and designed the experiments. C.Z., J.Q., S.Z., N.Z., Y.Z., and B.T. performed the experiments. B.D., C.Z., Q.W., S.S., and J.C. analyzed the data. B.D., S.S., and C.Z. wrote the manuscript.

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Correspondence to Mingyao Liu or Bing Du.

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Zhang, C., Qin, J., Zhang, S. et al. ADP/P2Y1 aggravates inflammatory bowel disease through ERK5-mediated NLRP3 inflammasome activation. Mucosal Immunol (2020). https://doi.org/10.1038/s41385-020-0307-5

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