Pannexin-1-mediated intracellular delivery of muramyl dipeptide induces caspase-1 activation via cryopyrin/NLRP3 independently of Nod2

Noemí Marina-García, Luigi Franchi, Yungi Kim, Douglas Miller, Christine McDonald, Geert Jan Boons, Gabriel Núñez

研究成果: Article

125 引用 (Scopus)

抄録

Muramyl dipeptide (MDP), the microbial activator of nucleotide-binding oligomerization domain 2 (Nod2), induces NF-κB and MAPK activation, leading to the production of multiple anti-bacterial and proinflammatory molecules. In addition, MDP has been implicated in IL-1β secretion through the regulation of caspase-1. However, the mechanisms that mediate caspase-1 activation and IL-1β secretion in response to MDP stimulation remain poorly understood. We show here that fluorescent MDP molecules are internalized in primary macrophages and accumulate in granular structures that colocalize with markers of acidified endosomal compartments. The uptake of MDP was Nod2-independent. Upon ATP stimulation, labeled MDP was rapidly released from acidified vesicles into the cytosol, a process that required functional pannexin-1. Caspase-1 activation induced by MDP and ATP required pannexin-1 and Cryopyrin but was independent of Nod2. Conversely, induction of pro-IL-1β mRNA by MDP stimulation was abolished in Nod2-deficient macrophages but unimpaired in macrophages lacking Cryopyrin. These studies demonstrate a Nod2-independent mechanism mediated through pore-forming pannexin-1 that is required for intracellular delivery of MDP to the cytosol and caspase-1 activation. Furthermore, the work provides evidence for distinct roles of Nod2 and Cryopyrin in the regulation of MDP-induced caspase-1 activation and IL-1β secretion.

元の言語English
ページ(範囲)4050-4057
ページ数8
ジャーナルJournal of Immunology
180
発行部数6
出版物ステータスPublished - 2008 3 15
外部発表Yes

Fingerprint

Acetylmuramyl-Alanyl-Isoglutamine
Caspase 1
Nucleotides
Interleukin-1
Macrophages
Cytosol
Adenosine Triphosphate

ASJC Scopus subject areas

  • Immunology

これを引用

Marina-García, N., Franchi, L., Kim, Y., Miller, D., McDonald, C., Boons, G. J., & Núñez, G. (2008). Pannexin-1-mediated intracellular delivery of muramyl dipeptide induces caspase-1 activation via cryopyrin/NLRP3 independently of Nod2. Journal of Immunology, 180(6), 4050-4057.

Pannexin-1-mediated intracellular delivery of muramyl dipeptide induces caspase-1 activation via cryopyrin/NLRP3 independently of Nod2. / Marina-García, Noemí; Franchi, Luigi; Kim, Yungi; Miller, Douglas; McDonald, Christine; Boons, Geert Jan; Núñez, Gabriel.

:: Journal of Immunology, 巻 180, 番号 6, 15.03.2008, p. 4050-4057.

研究成果: Article

Marina-García, N, Franchi, L, Kim, Y, Miller, D, McDonald, C, Boons, GJ & Núñez, G 2008, 'Pannexin-1-mediated intracellular delivery of muramyl dipeptide induces caspase-1 activation via cryopyrin/NLRP3 independently of Nod2', Journal of Immunology, 巻. 180, 番号 6, pp. 4050-4057.
Marina-García, Noemí ; Franchi, Luigi ; Kim, Yungi ; Miller, Douglas ; McDonald, Christine ; Boons, Geert Jan ; Núñez, Gabriel. / Pannexin-1-mediated intracellular delivery of muramyl dipeptide induces caspase-1 activation via cryopyrin/NLRP3 independently of Nod2. :: Journal of Immunology. 2008 ; 巻 180, 番号 6. pp. 4050-4057.
@article{f8eae48a85d14bc1b0ea24e393637723,
title = "Pannexin-1-mediated intracellular delivery of muramyl dipeptide induces caspase-1 activation via cryopyrin/NLRP3 independently of Nod2",
abstract = "Muramyl dipeptide (MDP), the microbial activator of nucleotide-binding oligomerization domain 2 (Nod2), induces NF-κB and MAPK activation, leading to the production of multiple anti-bacterial and proinflammatory molecules. In addition, MDP has been implicated in IL-1β secretion through the regulation of caspase-1. However, the mechanisms that mediate caspase-1 activation and IL-1β secretion in response to MDP stimulation remain poorly understood. We show here that fluorescent MDP molecules are internalized in primary macrophages and accumulate in granular structures that colocalize with markers of acidified endosomal compartments. The uptake of MDP was Nod2-independent. Upon ATP stimulation, labeled MDP was rapidly released from acidified vesicles into the cytosol, a process that required functional pannexin-1. Caspase-1 activation induced by MDP and ATP required pannexin-1 and Cryopyrin but was independent of Nod2. Conversely, induction of pro-IL-1β mRNA by MDP stimulation was abolished in Nod2-deficient macrophages but unimpaired in macrophages lacking Cryopyrin. These studies demonstrate a Nod2-independent mechanism mediated through pore-forming pannexin-1 that is required for intracellular delivery of MDP to the cytosol and caspase-1 activation. Furthermore, the work provides evidence for distinct roles of Nod2 and Cryopyrin in the regulation of MDP-induced caspase-1 activation and IL-1β secretion.",
author = "Noem{\'i} Marina-Garc{\'i}a and Luigi Franchi and Yungi Kim and Douglas Miller and Christine McDonald and Boons, {Geert Jan} and Gabriel N{\'u}{\~n}ez",
year = "2008",
month = "3",
day = "15",
language = "English",
volume = "180",
pages = "4050--4057",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "6",

}

TY - JOUR

T1 - Pannexin-1-mediated intracellular delivery of muramyl dipeptide induces caspase-1 activation via cryopyrin/NLRP3 independently of Nod2

AU - Marina-García, Noemí

AU - Franchi, Luigi

AU - Kim, Yungi

AU - Miller, Douglas

AU - McDonald, Christine

AU - Boons, Geert Jan

AU - Núñez, Gabriel

PY - 2008/3/15

Y1 - 2008/3/15

N2 - Muramyl dipeptide (MDP), the microbial activator of nucleotide-binding oligomerization domain 2 (Nod2), induces NF-κB and MAPK activation, leading to the production of multiple anti-bacterial and proinflammatory molecules. In addition, MDP has been implicated in IL-1β secretion through the regulation of caspase-1. However, the mechanisms that mediate caspase-1 activation and IL-1β secretion in response to MDP stimulation remain poorly understood. We show here that fluorescent MDP molecules are internalized in primary macrophages and accumulate in granular structures that colocalize with markers of acidified endosomal compartments. The uptake of MDP was Nod2-independent. Upon ATP stimulation, labeled MDP was rapidly released from acidified vesicles into the cytosol, a process that required functional pannexin-1. Caspase-1 activation induced by MDP and ATP required pannexin-1 and Cryopyrin but was independent of Nod2. Conversely, induction of pro-IL-1β mRNA by MDP stimulation was abolished in Nod2-deficient macrophages but unimpaired in macrophages lacking Cryopyrin. These studies demonstrate a Nod2-independent mechanism mediated through pore-forming pannexin-1 that is required for intracellular delivery of MDP to the cytosol and caspase-1 activation. Furthermore, the work provides evidence for distinct roles of Nod2 and Cryopyrin in the regulation of MDP-induced caspase-1 activation and IL-1β secretion.

AB - Muramyl dipeptide (MDP), the microbial activator of nucleotide-binding oligomerization domain 2 (Nod2), induces NF-κB and MAPK activation, leading to the production of multiple anti-bacterial and proinflammatory molecules. In addition, MDP has been implicated in IL-1β secretion through the regulation of caspase-1. However, the mechanisms that mediate caspase-1 activation and IL-1β secretion in response to MDP stimulation remain poorly understood. We show here that fluorescent MDP molecules are internalized in primary macrophages and accumulate in granular structures that colocalize with markers of acidified endosomal compartments. The uptake of MDP was Nod2-independent. Upon ATP stimulation, labeled MDP was rapidly released from acidified vesicles into the cytosol, a process that required functional pannexin-1. Caspase-1 activation induced by MDP and ATP required pannexin-1 and Cryopyrin but was independent of Nod2. Conversely, induction of pro-IL-1β mRNA by MDP stimulation was abolished in Nod2-deficient macrophages but unimpaired in macrophages lacking Cryopyrin. These studies demonstrate a Nod2-independent mechanism mediated through pore-forming pannexin-1 that is required for intracellular delivery of MDP to the cytosol and caspase-1 activation. Furthermore, the work provides evidence for distinct roles of Nod2 and Cryopyrin in the regulation of MDP-induced caspase-1 activation and IL-1β secretion.

UR - http://www.scopus.com/inward/record.url?scp=44849136632&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=44849136632&partnerID=8YFLogxK

M3 - Article

C2 - 18322214

AN - SCOPUS:44849136632

VL - 180

SP - 4050

EP - 4057

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 6

ER -