Identification of Bacterial Muramyl Dipeptide as Activator of the NALP3/Cryopyrin Inflammasome
Open accessAbstract
Activation of caspase-1 and subsequent processing and secretion of the pro-inflammatory cytokine IL-1beta is triggered upon assembly of the inflammasome complex. It is generally believed that bacterial lipopolysaccharides (LPS) are activators of the inflammasome through stimulation of Toll-like receptor 4 (TLR4). Like TLRs, NALP3/Cryopyrin, which is a key component of the inflammasome, contains Leucine-Rich-Repeats (LRRs). LRRs are frequently used to sense bacterial components, 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-1beta. 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-1beta 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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- Authors
- Martinon, F., Agostini, L., Meylan, E., & Tschopp, J.
- Affiliations
- University of Lausanne (CH)
- Corresponding author
- Tschopp, Jürg
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 2004-11
- Volume
- 14
- Issue
- 21
- Pages
- 1929-1934
- ISSN
- 0960-9822 (ISSN-L)
- OpenAlex
- W2075145828
- Cited by
- 579
- References
- 33
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 9 · 2023: 18 · 2022: 11 · 2021: 18 · 2020: 27 · 2019: 19 · 2018: 18 · 2017: 26 · 2016: 20 · 2015: 27 · 2014: 21 · 2013: 22 · 2012: 42
- FWCI
- 12.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 3211 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Keywords
- muramyl dipeptide, caspase-1 activation, IL-1β maturation, peptidoglycan, Muckle-Wells syndrome, macrophages, autoinflammatory disease, adjuvant effect, bacterial recognition
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Acetylmuramyl-Alanyl-Isoglutamine, Amyloidosis, Carrier Proteins, Cells, Cultured, Chromatography, Gel, Humans, Inflammation, Interleukin-1, Macrophages, Peptidoglycan, Plasmids, Syndrome, Urticaria, Autoimmunity, Caspase 1
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