NunezJImmunol2008 - Pannexin-1-Mediated Intracellular...

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Unformatted text preview: Pannexin-1-Mediated Intracellular Delivery of Muramyl Dipeptide Induces Caspase-1 Activation via Cryopyrin/NLRP3 Independently of Nod2 1 Noemı´ Marina-Garcı´a,* Luigi Franchi,* Yun-Gi Kim,* Douglas Miller, † Christine McDonald, 2 * Geert-Jan Boons, † and Gabriel Nu ´n ˜ez 3 * Muramyl dipeptide (MDP), the microbial activator of nucleotide-binding oligomerization domain 2 (Nod2), induces NF- k B and MAPK activation, leading to the production of multiple anti-bacterial and proinflammatory molecules. In addition, MDP has been implicated in IL-1 b secretion through the regulation of caspase-1. However, the mechanisms that mediate caspase-1 activation and IL-1 b 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 b 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 b secretion. The Journal of Immunology, 2008, 180: 4050–4057. I nterleukin-1 b (IL-1 b ) plays an important role in the induc- tion of immune responses and in the development of inflam- matory disease, fever, and septic shock (1). In response to proinflammatory stimuli, including pathogenic bacteria, the IL-1 b precursor is induced in monocytes and macrophages and processed into the biologically active IL-1 b molecule by caspase-1 (2–6). The protease caspase-1 is expressed in monocyte/macrophages as an inactive zymogen that is activated by self-cleavage by large multiprotein complexes named “inflammasomes” (7). Recent stud- ies have implicated members of the nucleotide-binding oligomer- ization domain (Nod) 4-like receptor (NLR) family in the activation of caspase-1 via the inflammasome (8). NLRs are intracellular pat- tern-recognition receptors that sense microbial structures that are common to a large number of microorganisms (9). Two NLR fam- ily members, Nod1 and Nod2, induce the activation of several host defense signaling pathways, including the NF- k B transcription factor and the MAPK, in response to bacterial molecules produced during the synthesis and/or degradation of peptidoglycan (10–14)....
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NunezJImmunol2008 - Pannexin-1-Mediated Intracellular...

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