NLRP3- Inflammasome

Last updated on: 25.11.2023

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DefinitionThis section has been translated automatically.

Inflammasomes are instruments of the innate immune system that are responsible for the activation of inflammatory reactions. Inflammasomes are cytosolic (intracellular) multi-protein complexes (Martinon F et al. 2002), which are predominantly found in immune cells, such as dendritic cells and macrophages, but also in epithelia of the skin and mucous membranes (intestinal and urinary bladder epithelia). Activation of the inflammasome promotes the proteolytic cleavage, maturation and secretion of the pro-inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18) as well as the cleavage of gas dermin D. The N-terminal fragment resulting from gasdermin D cleavage, triggers a pro-inflammatory form of programmed cell death of pyroptosis and is responsible for the secretion of mature cytokines, presumably through the formation of pores in the plasma membrane (Broz P et al. 2016). In addition, inflammasomes can also trigger a special form of programmed cell death, PANOptosis, which has essential features of apoptosis, pyroptosis and necroptosis (Zhuang L et al.2023).

Inflammasome activation is triggered by different types of cytosolic pattern recognition receptors (PRRs), either microbe-derived (pathogen-associated molecular patterns/PAMPs) or host cell-derived (damage-associated molecular patterns/DAMPs). The pattern recognition receptors involved in inflammasomes include so-called NLRs (nucleotide-binding oligomerization domain and leucine-rich repeat-containing receptors) as well as AIM2 (absent in melanoma 2), IFI16 (IFN-inducible protein 16) and pyrin (Broz P et al. 2016).

The inflammasome receptors interact with the adaptor protein ASC via their caspase activation and recruitment domain (CARD) or via the pyrin domain (PYD), which then activates caspase-1 via its CARD domain by proteolytic cleavage (Broz P et al. 2016). Finally, the activated caspase-1 cleaves the immature pro-inflammatory cytokines pro-IL-1beta and pro-IL-18 as well as gas dermin D into their active end stages. IL 1beta and IL 18 in particular are responsible for inflammatory signaling and pyroptotic cell death.

In addition to these so-called canonical inflammasomes, non-canonical inflammasome complexes have also been described that act independently of caspase-1. In animal experiments, non-canonical inflammasomes can be activated by direct recognition of cytosolic bacterial lipopolysaccharide (LPS). In human cells, the corresponding caspases of the non-canonical inflammasome are caspase 4 and caspase 5 (Broz P et al. 2016).

So far, inflammasomes have mainly been detected in professional immune cells of the innate immune system, such as macrophages and neutrophils. However, it is now known that inflammasome components are expressed in epithelial barrier tissues (Winsor N et al. 2019). In the case of dysregulation of inflammasome activation, this can lead to significant disorders of innate immunity, chronic inflammatory states, tumor formation, metabolic and neurodegenerative diseases (Ippagunta SK et al. 2011).

General informationThis section has been translated automatically.

NLRP3- Inflammasome: see also NLRP3. In addition to the NOD and LRR domains, NLRP3 contains a PYD domain like NLRP1 and therefore activates caspase-1 in the same way by using its PYD to recruit ASC. It forms only one oligomer per cell. Its oligomer consists of seven NLRP3 molecules. With a diameter of about 2 µm, the NLRP-3 inflammasome is the largest inflammasome known to date (Stutz A et al. 2009). The oligomerization of NLRP3 is triggered by a large number of stimuli, including both PAMPs and DAMPs. Examples of such stimuli from the DAMP group are crystalline substances such as urate crystals, alum or asbestos. It has also been found that the NLRP3 inflammasome reacts to PAMPs from various pathogens, such as viruses. Influenza A, bacteria, e.g. Neisseria gonorrhoeae and various bacterial toxins (Duncan JA et al. 2009).

All NLRP3 activators induce the efflux of cytosolic potassium from the cells. Activation of the NLRP3 inflammasome by cholesterol crystals and MSU crystals increases NLRP3-induced IL-1beta production (Jamilloux Y et al. 2014). It can be assumed that this process is abolished in arteriosclerosis and gout, so that these crystals can form in the cell. Inorganic particles such as titanium dioxide, silicon dioxide and asbestos can also trigger activation of the inflammasome (Yazdi AS et al. 2010).

NLRP3 mutations: Some genetically fixed diseases are associated with elevated serum levels of interleukin-1β. These autoimmune diseases are summarized under the generic term "hereditary periodic fever syndromes" (cryopyrin-associated-periodic syndromes - CAPS). These are syndromes with periodic episodes of fever and inflammation.

Gout and pseudogout: In recent years, gout and pseudogout have been linked to NLRP3 (Martinon F et al. 2006). The pathognetic principle for both diseases is the precipitation of uric acid or calcium pyrophosphate crystals in the joints, strong activators of NLRP3. The result is a marked release of IL-1beta.

Silicosis/asbestosis: An analogous mechanism applies to other crystalline substances such as silicon and asbestos dust. The uptake of these substances by alveolar macrophages leads to NLRP3-dependent increased production of IL-1β . Diesel soot particles or cigarette smoke also mediate NLRP3-dependent chronic pulomnal inflammatory processes.

Alzheimer's disease: Alzheimer's disease is a progressive, neurodegenerative disease of the cranial nerves characterized by the deposition of misfolded beta-amyloid peptide chains (Alzheimer's plaques) in the central nervous system. Phagocytizing cells of the microglia are stimulated to phagocytosis by beta-amyloid-containing plaques and release inflammatory cytokines.

Other NLRP3-associated diseases:

Contact allergy: This type IV reaction has been associated with activation of IL-1β and IL-18 by the NLRP3 inflammasome. An example of this reaction mechanism has been demonstrated in contact sensitization with 2,4-dinitrochlorobenzene (Watanabe H et al. 2007).

Psoriasis: In psoriasis, the body's own cytosolic DNA activates the AIM2 inflammasome in the epithelial cells of the skin and thus initiates the inflammatory cascade.

LiteratureThis section has been translated automatically.

  1. Broz P et al. (2016) Inflammasomes: mechanism of assembly, regulation and signaling. Nature Reviews. Immunology 16: 407-420.
  2. Duncan JA et al. (2009) Neisseria gonorrhoeae activates the proteinase cathepsin B to mediate the signaling activities of the NLRP3 and ASC-containing inflammasome. Journal of Immunology 182: 6460-6469.
  3. Fattinger SA et al. (2021) Epithelium-autonomous NAIP/NLRC4 prevents TNF-driven inflammatory destruction of the gut epithelial barrier in Salmonella-infected mice. Mucosal Immunology 14: 615-629.
  4. Ippagunta SK et al. (2011) The inflammasome adaptor ASC regulates the function of adaptive immune cells by controlling Dock2-mediated Rac activation and actin polymerization. Nature Immunology 12: 1010-1016
  5. Martinon F et al. (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Molecular Cell 10: 417-426.
  6. Martinon F et al. (2006) Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440: 237-241.
  7. Sellin ME et al. (2015) Inflammasomes of the intestinal epithelium. Trends in Immunology 36: 442-450.
  8. Sellin ME et al. (2018) Consequences of Epithelial Inflammasome Activation by Bacterial Pathogens. Journal of Molecular Biology. Mechanisms of Inflammasome Activation 430: 193-206.
  9. Stutz A et al. (2009) Inflammasomes: too big to miss. The Journal of Clinical Investigation 119: 3502-3511.
  10. Winsor N et al. (2019) Canonical and noncanonical inflammasomes in intestinal epithelial cells. Cellular Microbiology 21: e13079.
  11. Yazdi AS et al.(2010) Nanoparticles activate the NLR pyrin domain containing 3 (Nlrp3) inflammasome and cause pulmonary inflammation through release of IL-1α
  12. Zhuang L et al.(2023) A comprehensive analysis of PANoptosome to prognosis and immunotherapy response in pan-cancer. Sci Rep 13:3877.

Last updated on: 25.11.2023