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 language | English (US) |
|---|---|
| Pages (from-to) | 3490-3503 |
| Number of pages | 14 |
| Journal | Journal of Clinical Investigation |
| Volume | 128 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 1 2018 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Medicine(all)
Cite this
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 journal › Article
}
TY - JOUR
T1 - P2X7R mutation disrupts the NLRP3-mediated Th program and predicts poor cardiac allograft outcomes
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
PY - 2018/8/1
Y1 - 2018/8/1
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.
AB - 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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U2 - 10.1172/JCI94524
DO - 10.1172/JCI94524
M3 - Article
VL - 128
SP - 3490
EP - 3503
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 8
ER -