Abstract
Inflammasomes are supramolecular protein complexes implicated in the detection of pathogens or danger-associated molecules and are responsible for mounting the first line of innate immune response to counteract these signals and restore tissue homeostasis. Among different inflammasomes identified so far, NLRP3 is of main interest since mutations in Nlrp3 gene are associated with autoinflammatory diseases such as Muckle–Wells syndrome, neonatal onset multisystem inflammatory disease, and familial cold urticaria/autoinflammatory syndrome. On the other hand, whereas other inflammasomes are mainly detectors of specific molecular motifs, NLRP3 is acting as a general sensor of cellular perturbations including potassium efflux, lysosomal damage, and ROS production. Besides this central role of NLRP3 in inflammation, recent publications show that the NLRP3 inflammasome is also involved in the physiopathology of several neurological disorders including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. This review gives an overview of the established functions of the NLRP3 inflammasome in mediating inflammation in macrophages and describes its recently discovered roles in neurological disorders in promoting neuroinflammation, as well as modulating key proteins mediating the disorders. Finally, we discuss the targeting of NLRP3 in neurological diseases and present some examples of NLRP3 inhibitors that could be used in neurological disorder treatments.
Highlights
Upon its stimulation by ion flux triggering molecules such as ATP and nigericin or monosodium urate crystals (MSU), NLRP3 forms a supramolecular complex with the adaptor protein ASC that in turn recruits the effector protease caspase-1 to constitute a multiprotein complex, otherwise known as “specks”, that serves as a platform for the nucleation of the inflammasome (Sehlik et al, 2003)
Up to now, NLRP3 inflammasome research was limited to macrophages and especially to mouse bone marrowderived or human peripheral blood mononuclear cellderived macrophages or human leukemia cell line THP-1
Recent findings clearly show that NLRP3 inflammasome components are expressed in a variety of other cell types including neutrophils, epithelial and endothelial cells and in some tissue-resident macrophages, such as microglia in the brain, Kupffer cells in the liver, and Langerhans cells in the skin
Summary
Several inflammasomes activated by specific ligands have been described so far: NLRP3, Pyrin, NLRP1, NLRC4, and AIM2 are induced, among other stimulants, by ATP (Mariathasan et al, 2006), Clostridium difficile (Xu et al, 2014), muramyl dipeptide (Hsu et al, 2008), bacterial flagellin (Sutterwala et al, 2007), and polydA:dT (Hornung et al, 2009), respectively Induction of these inflammasomes triggers the proteolytic cleavage of caspase-1 that in turn cleaves the proforms of IL-1β, IL-18, and gasdermin D into their active mature forms. Pathological neuroinflammation is caused by abnormally high cytokine/chemokine secretion due to an excessive amount of stimulants (Alzheimer’s and Parkinson’s diseases), infection (meningitis) or physical or mechanical injuries (traumatic brain injuries), and vascular occlusions resulting in an excessive inflammasome activation, dysregulation of blood brain barrier (BBB) permeability or BBB breakdown, and increased infiltration of peripheral immune cells.
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