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

The Journal of Clinical Investigation
Francesca D'AddioPaolo Fiorina

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.

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Citations

Oct 13, 2019·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·Scott YeudallVictor E Laubach
Aug 23, 2019·Physiological Reviews·Volker VallonBellamkonda K Kishore
Jun 26, 2020·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·Chao WeiWeiyun Shi
Aug 21, 2019·Cell Communication and Signaling : CCS·Pingping MaWanqian Liu
Mar 10, 2021·Journal of Endocrinological Investigation·L MontefuscoP Fiorina
Mar 26, 2021·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·Vera UsuelliPaolo Fiorina
May 18, 2021·Frontiers in Pharmacology·Junteng ZhouXin Cao

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Methods Mentioned

BETA
genotyping
PCR
immunoprecipitation
ubiquitination
Exome Sequencing
transgenic
Assay
PMA
FACS
ELISA

Software Mentioned

TASSER
FlowJo
RT 2 profiler PCR Array Data Analysis

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