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

被引：40

作者：

D'Addio, Francesca ^{[1
]}

Vergani, Andrea ^{[2
]}

Potena, Luciano ^{[3
]}

Maestroni, Anna ^{[1
]}

Usuelli, Vera ^{[2
]}

Ben Nasr, Moufida ^{[1
,2
]}

Bassi, Roberto ^{[2
]}

Tezza, Sara ^{[2
]}

Dellepiane, Sergio ^{[2
]}

El Essawy, Basset ^{[4
,5
]}

Iascone, Maria ^{[6
]}

Iacovoni, Attilio ^{[7
]}

Borgese, Laura ^{[3
]}

Liu, Kaifeng ^{[8
]}

Visner, Gary ^{[8
]}

Dhe-Paganon, Sirano ^{[9
]}

Corradi, Domenico ^{[10
]}

Abdi, Reza ^{[5
]}

Starling, Randall C. ^{[11
]}

Folli, Franco ^{[12
]}

Zuccotti, Gian Vincenzo ^{[1
,13
]}

Sayegh, Mohamed H. ^{[14
]}

Heeger, Peter S. ^{[15
,16
]}

Chandraker, Anil ^{[5
]}

Grigioni, Francesco ^{[3
]}

Fiorina, Paolo ^{[1
,2
,17
]}

机构：

[1] Univ Milan, L Sacco Dept Biomed & Clin Sci, Pediat Clin Res Ctr Romeo Enrica Invernizzi, Int Ctr Type Diabet 1, Milan, Italy

[2] Harvard Med Sch, Boston Childrens Hosp, Nephrol Div, 300 Longwood Ave,Enders Bldg 5th Floor En511, Boston, MA 02115 USA

[3] Alma Mater Univ Bologna, Dept Expt Diagnost & Specialty Med, Heart Failure & Heart Transplant Program, Bologna, Italy

[4] Al Azhar Univ, Med, Cairo, Egypt

[5] Brigham & Womens Hosp, Nephrol Div, Transplantat Res Ctr, 75 Francis St, Boston, MA 02115 USA

[6] ASST Papa Giovanni XXIII, Lab Genet Med, Bergamo, Italy

[7] ASST Papa Giovanni XXIII, Dipartimento Cardiovasc, Bergamo, Italy

[8] Boston Childrens Hosp, Div Resp Dis, Boston, MA USA

[9] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[10] Univ Parma, Dept Biomed Biotechnol & Translat Sci, Unit Pathol, Parma, Italy

[11] Cleveland Clin, Heart & Vasc Inst, Heart Failure Ctr, Cleveland, OH 44106 USA

[12] Univ Milan, ASST Santi Paolo & Carlo, Dept Hlth Sci, Endocrinol & Metab, Milan, Italy

[13] Childrens Hosp Buzzi, Dept Pediat, Milan, Italy

[14] Amer Univ Beirut, Beirut, Lebanon

[15] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA

[16] Icahn Sch Med Mt Sinai, Translat Transplant Res Ctr, New York, NY 10029 USA

[17] ASST Fatebenefratelli Sacco, Endocrinol Div, Milan, Italy

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2018年 / 128卷 / 08期

关键词：

HUMAN P2X(7) RECEPTOR; NLRP3; INFLAMMASOME; PURINERGIC RECEPTORS; CELL PROLIFERATION; EMERGING ROLE; ATP; TRANSPLANTATION; POLYMORPHISM; DISEASE; RESPONSES;

D O I：

10.1172/JCI94524

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页码：3490 / 3503

页数：14

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