Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 10.05.2022

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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), along with the NOD1 and NOD2 proteins, are members of the NLR (Nod-like recept or ) protein family and play a major role in innate immunity as pathogen recognition receptors (PPRs). NLRPs, like NOD proteins, are expressed exclusively cytoplasmically. All NLRPs (they all contain a pyrin domain) are encoded by a common gene family in humans. 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 referred to as CIAS1 ) located on chromosome 1q44. NLRP3, like NLRP1, NLRP2, NLRC4 and AIM-2, is one of the proteins that make up inflammasomes.

Inflammasomes are variously assembled cytosolic protein complexes, with the different NLRPs playing a weighty role in their functionality. Inflammasomes are predominantly found in immune cells such as dendritic cells and macrophages. The NLRP3 inflamm asome is among the most biologically important inflammasome complexes. Imiquimod activates the NLRP3 inflammasome. Imiquimod interferes with the respiratory chain of the cells releasing massive amounts of oxygen radicals. Hereby a critical threshold is exceeded; an activation of NLRP3 occurs.

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

General information
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NLRP3 inflammasome-associated diseases:

The innate immune system possesses two pathogen recognition systems, Toll-like receptors and cytosolic NLRs, for rapid and nonspecific 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 IL-1beta and IL-18. These can be different pathogens such as extracellular ATP (from destroyed or activated cells), such as crystalline structures (asbestos, silicon oxide, uric acid, calcium pyrophosphate or cholesterol crystals) or reactive oxygen species (ROS).

All substances have in common that they lead to NLRP3 activation and thus induce the release of IL-1beta. After IL-1beta is released in bioactive form, IL-1beta binds to its receptor (IL-1R) and initiates inflammatory responses of various types (Dinarello CA 2009).

NLRP3 mutations: Some genetically fixed diseases are associated with elevated serum levels of interleukin-1β. These autoimmune diseases are grouped under the umbrella 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). For both diseases, the pathognetic principle is the precipitation of uric acid or calcium pyrophosphate crystals in the joints, strong activators of NLRP3. The consequence is a marked release of IL-1beta.

Silicosis/asbestosis: For other crystalline substances, such as silicon and asbestos dust, an analogous mechanism applies. Uptake of these substances by alveolar macrophages leads to increased production of IL-1β in an NLRP3-dependent manner (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 deposition of misfolded beta-amyloid peptide chains (Alzheimer's plaques) in the central nervous system. Phagocytosing cells of microglia are stimulated to phagocytosis by beta-amyloid-containing plaques and secrete 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. An example at this reaction mechanism has been demonstrated is contact sensitization with 2,4-dinitrochlorobenzene (Watanabe H et al. 2007).

Psoriasis: In psoriasis, endogenous cytosolic DNA activates the AIM2 inflammasome in skin epithelial cells, initiating the inflammatory cascade.

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Last updated on: 10.05.2022