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

被引:130
作者
Marina-Garcia, Noemi [1 ,2 ]
Franchi, Luigi [1 ,2 ]
Kim, Yun-Gi [1 ,2 ]
Miller, Douglas [3 ]
McDonald, Christine [1 ,2 ]
Boons, Geert-Jan [3 ]
Nunez, Gabriel [1 ,2 ]
机构
[1] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA
[2] Ctr Comprehens Canc, Ann Arbor, MI 48109 USA
[3] Univ Georgia, Complex Carbohydrate Res Ctr, Athens, GA 30602 USA
关键词
D O I
10.4049/jimmunol.180.6.4050
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Muramyl dipeptide (MDP), the microbial activator of nucleotide-binding oligomerization domain 2 (Nod2), induces NF-kappa B and MAPK activation, leading to the production of multiple anti-bacterial and proinflammatory molecules. In addition, MDP has been implicated in IL-1 beta secretion through the regulation of caspase-1. However, the mechanisms that mediate caspase-1 activation and IL-1 beta 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-1 beta 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-1 beta secretion.
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页码:4050 / 4057
页数:8
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