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What is NLRP3?

NLRP3 Inflammasome

Among the inflammasomes, NLRP3 inflammasome is the most studied.

Its activation in macrophages can be achieved with a plethora of PAMPs, such as liposaccharide, peptidoglycan, and bacterial nucleic acids, provided the cells are exposed to ATP.

Indeed, in the absence of ATP, macrophages stimulated with LPS produce large quantities of pro-IL-1β, but release little mature cytokine to the medium. ATP and certain bacterial toxins, such as nigericin and maitotoxin, cause a change in the intracellular ion composition leading to the activation of the NLRP3 inflammasome.

The effect of ATP is mediated by the purinergic P2X7 receptor together with pannexin, which causes a rapid potassium efflux from the cytosol upon activation [1].

Crystals of monosodium urate (MSU) and calcium phosphate dihydrate (CPPD) are known to activate caspase-1 in a NLRP3-dependent manner [2]. Deposition of MSU and CPPD crystals in joints is responsible for the inflammatory conditions gout and pseudogout, respectively, implicating NLRP3 in their etiology. Uric acid in addition is released into the extracellular milieu by necrotic cells, suggesting an important role of NLRP3 in the detection of endogenous ‘danger’ signal.

Crystalline silica and asbestos are known to activate the NLRP3 inflammasome, implicating its role in the pathogenesis of silicosis and asbestosis [3,4,5].

Aluminium salt (alum) can also activate the NLRP3 inflammasome, albeit in the presence of PAMPs such as LPS [5,6,7].

Phagocytosis of crystals leads to lysosomal swelling and damage. The lysosomal perturbation together with the release of cathepsin B, a lysosomal cysteine protease, result in the activation of the NLRP3 inflammasome [5].

NALP3 inflammasome, composed of the three proteins NALP3, ASC, and Caspase-1, is a macromolecular complex responsible for the innate immune response against infection with bacterial and viral pathogens. Formation of the inflammasome can lead to the activation of inflammatory caspases, such as Caspase-1, which then activate pro-inflammatory cytokines by proteolytic cleavage. The assembly of the NALP3 inflammasome depends on the protein-interacting domain known as the death domain superfamily. NALP3 inflammasome is assembled via a pyrin domain (PYD)/PYD interaction between ASC and NALP3 and a caspase recruitment domain/caspase recruitment domain interaction between ASC and Caspase-1. As a first step toward elucidating the molecular mechanisms of inflammatory caspase activation by formation of inflammasome, we report the crystal structure of the PYD from NALP3 at 1.7-Å resolution. Although NALP3 PYD has the canonical six-helical bundle structural fold similar to other PYDs, the high resolution structure reveals the possible biologically important homodimeric interface and the dynamic properties of the fold. Comparison with other PYD structures shows both similarities and differences that may be functionally relevant. Structural and sequence analyses further implicate conserved surface residues in NALP3 PYD for ASC interaction and inflammasome assembly. The most interesting aspect of the structure was the unexpected disulfide bond between Cys-8 and Cys-108, which might be important for regulation of the activity of NALP3 by redox potential

[1] Pelegrin P, & Surprenant A., 2007. Pannexin-1 couples to maitotoxin- and nigericin-induced interleukin-1beta release through a dye uptake-independent pathway. J Biol Chem. 282(4):2386-94.
[2] Kanneganti TD, et al., 2007. Pannexin-1-mediated recognition of bacterial molecules activates the cryopyrin inflammasome independent of Toll-like receptor signaling. Immunity. 26(4):433-43.
[3] Martinon F. et al., 2006. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 440(7081):237-41.
[4] Dostert C. et al., 2008. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science. 320(5876):674-7.
[5] Cassel SL. et al., 2008. The Nalp3 inflammasome is essential for the development of silicosis. Proc Natl Acad Sci U S A. 105(26):9035-40.
[6] Hornung V. et al., 2008. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol. 9(8):847-56.
[7] Eisenbarth SC. et al., 2008. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature. 453(7198):1122-6.