NLRP3 protein

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 02.12.2023

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AGTAVPRL; AII; AVP; C1orf7; CIAS1; CLR1.1; Cryopyrin; FCAS; FCAS1; FCU; MWS; NALP3; NLR family; NLR family pyrin domain containing 3; PYPAF1; pyrin domain containing 3

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NLRPs (acronym for "NACHT, LRR and PYD domains-containing protein), together with the NOD1 and NOD2 proteins, are members of the NLR (Nod-like receptor) protein family and play a major role in innate immunity as pathogen recognition receptors (PPRs). Like the NOD proteins, NLRPs are exclusively expressed cytoplasmically. In humans, all NLRPs (they all contain a pyrin domain) are encoded by a common gene family. NLRPs are characterized by their ability to activate the different inflammasome complexes.

NLRP3 is a cytosolic protein that in humans is encoded by the NLRP3 gene (also known as CIAS1 ) located on chromosome 1q44. Like NLRP1, NLRP2, NLRC4 and AIM2, NLRP3 is one of the proteins that make up inflammasomes.

Inflammasomes are cytosolic protein complexes with different compositions, whereby the various NLRPs play an important role in their functionality. Inflammasomes are predominantly found in immune cells such as dendritic cells and macrophages.

The NLRP3 inflammasome is one of the biologically most important inflammasome complexes. Imiquimod activates the NLRP3 inflammasome. Imiquimod intervenes in the respiratory chain of the cells, releasing massive amounts of oxygen radicals. A critical threshold is exceeded and NLRP3 is activated.

The activation of an inflammasome complex leads to the expression of various caspases that convert inactive interleukin-1beta and interleukin-18 into their active form.

General information
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NLRP3 inflammasome-associated diseases:

With the Toll-like receptors and the cytosolic NLRs, the innate immune system has two pathogen recognition systems for the rapid and non-specific defense against pathogens.

DAMPs (Danger-associated molecular pattern): The binding of non-microbial pathogens -DAMPs- can also lead to the release of inflammatory mediators such as interleukin-1beta and interleukin-18. These can be different pathogens such as extracellular ATP (from destroyed or activated cells), crystalline structures (asbestos, silicon oxide, uric acid, calcium pyrophosphate or cholesterol crystals) or reactive oxygen species (ROS). What all substances have in common is that they lead to NLRP3 activation and thus induce the release of interleukin-1beta. After interleukin-1beta has been released in bioactive form, the cytokine binds to its receptor (IL1 receptor) and initiates inflammatory reactions of various kinds (Dinarello CA 2009).

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 periodically occurring bouts of fever and inflammation. The family of cold-induced autoinflammatory syndromes also belongs to this mutation family.

Gout and pseudogout: In recent years, gout and pseudogout have been linked to NLRP3 (Martinon F et al. 2006). For both diseases, the pathognetic principle 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 (Rimal B et al. 2005). Diesel soot particles or cigarette smoke also mediate NLRP3-dependent chronic pulomnal inflammatory processes.

Alzheimer's disease: Alzheimer's disease as a progressive, neurodegenerative disease of the cranial nerves is 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 (Simard AR et al. 2006).

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. One example in which this reaction mechanism has been demonstrated is 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.

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Last updated on: 02.12.2023