P2X7R mutation disrupts the NLRP3-mediated Th program and predicts poor cardiac allograft outcomes

Francesca D'Addio, Andrea Vergani, Luciano Potena, Anna Maestroni, Vera Usuelli, Moufida Ben Nasr, Roberto Bassi, Sara Tezza, Sergio Dellepiane, Basset El Essawy, Maria Iascone, Attilio Iacovoni, Laura Borgese, Kaifeng Liu, Gary Visner, Sirano Dhe-Paganon, Domenico Corradi, Reza Abdi, Randall C. Starling, Franco Folli & 6 others Gian Vincenzo Zuccotti, Mohamed H. Sayegh, Peter S. Heeger, Anil Chandraker, Francesco Grigioni, Paolo Fiorina

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3490-3503
Number of pages14
JournalJournal of Clinical Investigation
Volume128
Issue number8
DOIs
StatePublished - Aug 1 2018
Externally publishedYes

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Allografts
Mutation
T-Lymphocytes
Purinergic Receptors
Interleukin-17
NLR Proteins
Alleles

ASJC Scopus subject areas

  • Medicine(all)

Cite this

D'Addio, F., Vergani, A., Potena, L., Maestroni, A., Usuelli, V., Ben Nasr, M., ... Fiorina, P. (2018). P2X7R mutation disrupts the NLRP3-mediated Th program and predicts poor cardiac allograft outcomes. Journal of Clinical Investigation, 128(8), 3490-3503. https://doi.org/10.1172/JCI94524

P2X7R mutation disrupts the NLRP3-mediated Th program and predicts poor cardiac allograft outcomes. / D'Addio, Francesca; Vergani, Andrea; Potena, Luciano; Maestroni, Anna; Usuelli, Vera; Ben Nasr, Moufida; Bassi, Roberto; Tezza, Sara; Dellepiane, Sergio; El Essawy, Basset; Iascone, Maria; Iacovoni, Attilio; Borgese, Laura; Liu, Kaifeng; Visner, Gary; Dhe-Paganon, Sirano; Corradi, Domenico; Abdi, Reza; Starling, Randall C.; Folli, Franco; Zuccotti, Gian Vincenzo; Sayegh, Mohamed H.; Heeger, Peter S.; Chandraker, Anil; Grigioni, Francesco; Fiorina, Paolo.

In: Journal of Clinical Investigation, Vol. 128, No. 8, 01.08.2018, p. 3490-3503.

Research output: Contribution to journalArticle

D'Addio, F, Vergani, A, Potena, L, Maestroni, A, Usuelli, V, Ben Nasr, M, Bassi, R, Tezza, S, Dellepiane, S, El Essawy, B, Iascone, M, Iacovoni, A, Borgese, L, Liu, K, Visner, G, Dhe-Paganon, S, Corradi, D, Abdi, R, Starling, RC, Folli, F, Zuccotti, GV, Sayegh, MH, Heeger, PS, Chandraker, A, Grigioni, F & Fiorina, P 2018, 'P2X7R mutation disrupts the NLRP3-mediated Th program and predicts poor cardiac allograft outcomes', Journal of Clinical Investigation, vol. 128, no. 8, pp. 3490-3503. https://doi.org/10.1172/JCI94524
D'Addio, Francesca ; Vergani, Andrea ; Potena, Luciano ; Maestroni, Anna ; Usuelli, Vera ; Ben Nasr, Moufida ; Bassi, Roberto ; Tezza, Sara ; Dellepiane, Sergio ; El Essawy, Basset ; Iascone, Maria ; Iacovoni, Attilio ; Borgese, Laura ; Liu, Kaifeng ; Visner, Gary ; Dhe-Paganon, Sirano ; Corradi, Domenico ; Abdi, Reza ; Starling, Randall C. ; Folli, Franco ; Zuccotti, Gian Vincenzo ; Sayegh, Mohamed H. ; Heeger, Peter S. ; Chandraker, Anil ; Grigioni, Francesco ; Fiorina, Paolo. / P2X7R mutation disrupts the NLRP3-mediated Th program and predicts poor cardiac allograft outcomes. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 8. pp. 3490-3503.
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AU - D'Addio, Francesca

AU - Vergani, Andrea

AU - Potena, Luciano

AU - Maestroni, Anna

AU - Usuelli, Vera

AU - Ben Nasr, Moufida

AU - Bassi, Roberto

AU - Tezza, Sara

AU - Dellepiane, Sergio

AU - El Essawy, Basset

AU - Iascone, Maria

AU - Iacovoni, Attilio

AU - Borgese, Laura

AU - Liu, Kaifeng

AU - Visner, Gary

AU - Dhe-Paganon, Sirano

AU - Corradi, Domenico

AU - Abdi, Reza

AU - Starling, Randall C.

AU - Folli, Franco

AU - Zuccotti, Gian Vincenzo

AU - Sayegh, Mohamed H.

AU - Heeger, Peter S.

AU - Chandraker, Anil

AU - Grigioni, Francesco

AU - Fiorina, Paolo

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N2 - 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.

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