The DNA Inflammasome in Human Myeloid Cells Is Initiated by a STING-Cell Death Program Upstream of NLRP3

被引：554

作者：

Gaidt, Moritz M. ^{[1
,2
]}

Ebert, Thomas S. ^{[1
,2
]}

Chauhan, Dhruv ^{[1
,2
]}

Ramshorn, Katharina ^{[1
,2
]}

Pinci, Francesca ^{[1
,2
]}

Zuber, Sarah ^{[1
,2
]}

O'Duill, Fionan ^{[1
,2
,3
]}

Schmid-Burgk, Jonathan L. ^{[1
,2
,9
]}

Hoss, Florian

Buhmann, Raymund ^{[4
]}

Wittmann, Georg ^{[4
]}

Latz, Eicke ^{[3
,5
]}

Subklewe, Marion ^{[6
,7
]}

Hornung, Veit ^{[1
,2
,8
]}

机构：

[1] Ludwig Maximilians Univ Munchen, Gene Ctr, D-81377 Munich, Germany

[2] Ludwig Maximilians Univ Munchen, Dept Biochem, D-81377 Munich, Germany

[3] Univ Bonn, Univ Hosp, Inst Innate Immun, D-53127 Bonn, Germany

[4] Ludwig Maximilians Univ Munchen, Univ Hosp, Dept Transfus Med, D-81377 Munich, Germany

[5] Univ Massachusetts, Sch Med, Dept Infect Dis & Immunol, Worcester, MA 01655 USA

[6] Ludwig Maximilians Univ Munchen, Gene Ctr, Lab Translat Canc Immunol, D-81377 Munich, Germany

[7] Ludwig Maximilians Univ Munchen, Univ Hosp, Dept Med 3, D-81377 Munich, Germany

[8] Ludwig Maximilians Univ Munchen, Ctr Integrated Prot Sci CIPSM, D-81377 Munich, Germany

[9] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

来源：

CELL | 2017年 / 171卷 / 05期

关键词：

AIM2; INFLAMMASOME; ACTIVATION; DEFICIENT; AUTOPHAGY; INFECTION; MECHANISM; IMMUNITY; BACTERIA; TRIGGER; BLOC-1;

D O I：

10.1016/j.cell.2017.09.039

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Detection of cytosolic DNA constitutes a central event in the context of numerous infectious and sterile inflammatory conditions. Recent studies have uncovered a bipartite mode of cytosolic DNA recognition, in which the cGAS-STING axis triggers antiviral immunity, whereas AIM2 triggers inflamma-some activation. Here, we show that AIM2 is dispensable for DNA-mediated inflammasome activation in human myeloid cells. Instead, detection of cytosolic DNA by the cGAS-STING axis induces a cell death program initiating potassium efflux upstream of NLRP3. Forward genetics identified regulators of lysosomal trafficking to modulate this cell death program, and subsequent studies revealed that activated STING traffics to the lysosome, where it triggers membrane permeabilization and thus lysosomal cell death (LCD). Importantly, the cGAS-STING-NLRP3 pathway constitutes the default inflammasome response during viral and bacterial infections in human myeloid cells. We conclude that targeting the cGAS-STING-LCD-NLRP3 pathway will ameliorate pathology in inflammatory conditions that are associated with cytosolic DNA sensing.

引用

页码：1110 / +

页数：33

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