P2X7R mutation disrupts the NLRP3-mediated Th program and predicts poor cardiac allograft outcomes
| العنوان: | P2X7R mutation disrupts the NLRP3-mediated Th program and predicts poor cardiac allograft outcomes |
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| المؤلفون: | Sergio Dellepiane, Roberto Bassi, Basset El Essawy, Gian Vincenzo Zuccotti, Maria Iascone, Andrea Vergani, Mohamed H. Sayegh, Peter S. Heeger, Reza Abdi, Sara Tezza, Sirano Dhe-Paganon, Domenico Corradi, Randall C. Starling, Luciano Potena, Moufida Ben Nasr, Franco Folli, L. Borgese, Gary A. Visner, Attilio Iacovoni, Paolo Fiorina, Francesco Grigioni, Francesca D'Addio, Anil Chandraker, Kaifeng Liu, Vera Usuelli, Anna Maestroni |
| المصدر: | Journal of Clinical Investigation. 128:3490-3503 |
| بيانات النشر: | American Society for Clinical Investigation, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Graft Rejection, 0301 basic medicine, Mutant, 030230 surgery, Biology, medicine.disease_cause, 03 medical and health sciences, Th2 Cells, 0302 clinical medicine, NLR Family, Pyrin Domain-Containing 3 Protein, medicine, Humans, Gene silencing, Precision Medicine, Receptor, Mutation, integumentary system, Purinergic receptor, General Medicine, Allografts, Blockade, Transplantation, 030104 developmental biology, Cancer research, Heart Transplantation, Th17 Cells, Female, Receptors, Purinergic P2X7, Intracellular, Research Article |
| الوصف: | Purinergic receptor-7 (P2X7R) signaling controls Th17 and Th1 generation/differentiation, while NOD-like receptor P3 (NLRP3) acts as a Th2 transcriptional factor. Here, we demonstrated the existence of a P2X7R/NLRP3 pathway in T cells that is dysregulated by a P2X7R intracellular region loss-of-function mutation, leading to NLRP3 displacement and to excessive Th17 generation due to abrogation of the NLRP3-mediated Th2 program. This ultimately resulted in poor outcomes in cardiac-transplanted patients carrying the mutant allele, who showed abnormal Th17 generation. Transient NLRP3 silencing in nonmutant T cells or overexpression in mutant T cells normalized the Th profile. Interestingly, IL-17 blockade reduced Th17 skewing of human T cells in vitro and abrogated the severe allograft vasculopathy and abnormal Th17 generation observed in preclinical models in which P2X7R was genetically deleted. This P2X7R intracellular region mutation thus impaired the modulatory effects of P2X7R on NLRP3 expression and function in T cells and led to NLRP3 dysregulation and Th17 skewing, delineating a high-risk group of cardiac-transplanted patients who may benefit from personalized therapy. |
| تدمد: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci94524 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7ec02d204db7c78faa6233c468851122 https://doi.org/10.1172/jci94524 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....7ec02d204db7c78faa6233c468851122 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15588238 00219738 |
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| DOI: | 10.1172/jci94524 |