Current Biology
Volume 14, Issue 21, 9 November 2004, Pages 1929-1934
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Identification of Bacterial Muramyl Dipeptide as Activator of the NALP3/Cryopyrin Inflammasome

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Abstract

Activation of caspase-1 and subsequent processing and secretion of the pro-inflammatory cytokine IL-1β is triggered upon assembly of the inflammasome complex [1]. It is generally believed that bacterial lipopolysaccharides (LPS) are activators of the inflammasome through stimulation of Toll-like receptor 4 (TLR4) [2]. Like TLRs, NALP3/Cryopyrin, which is a key component of the inflammasome [3], contains Leucine-Rich-Repeats (LRRs). LRRs are frequently used to sense bacterial components 1, 4, 5, thus raising the possibility that bacteria directly activate the inflammasome. Here, we show that bacterial peptidoglycans (PGN), but surprisingly not LPS, induce NALP3-mediated activation of caspase-1 and maturation of proIL-1β. Activation is independent of TLRs because the PGN degradation product muramyl dipeptide (MDP), which is not sensed by TLRs, is the minimal-activating structure. Macrophages from a patient with Muckle-Wells syndrome, an autoinflammatory disease associated with mutations in the NALP3/Cryopyrin gene, show increased IL-1β secretion in the presence of MDP. The activation of the NALP3-inflammasome by MDP may be the basis of the potent adjuvant activity of MDP.

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