The NLRP3 inflammasome: a new player in neurological diseases

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.

Keywords: Alzheimer’s disease; NLRP3; Parkinson’s disease; inflammasomes.

Figure 1

Activation mechanisms of the NLRP3 inflammasome. The NLRP3 inflammasome requires two signals to be activated: the priming signal conferred by stimulation of TLRs by LPS and subsequent induction of inflammasome components’ gene expression through the NFkB pathway and secondly, an activatory signal that triggers the oligomerization of the complex NLRP3 with ASC and Caspase-1; that could be either ROS production by the mitochondria induced by Imiquimod, potassium efflux resulting from ATP or Nigericin stimulation or lysosomal rupture triggered by phagocytosed crystals. The NLRP3 inflammasome is also indirectly activated through the noncanonical inflammasome formed by caspase-4/5 that senses lipopolysaccharide from gram-negative bacteria. LPS: Lipopolysaccharide; TLR: Toll-like receptor; ROS: Recative oxygen species; ATP: Adenosine triphosphate

Figure 2

The NLRP3 inflammasome in neurological disorders and novel inhibitor drugs. The NLRP3 inflammasome is activated in reponse to several neurological disorder-triggering molecules. While β-amyloid and α-synuclein, implicated in Alzheimer’s and Parkinson’s disorders respectively, induce lysosomal rupture and Cathepsin B-dependent NLRP3 inflammasome activation; danger associated molecular patterns (or DAMPs) released during traumatic brain injury trigger ROS-dependent NLRP3 inflammasome activation. Different inhibitory molecules of the NLRP3 inflammasome that resulted in the improvement in the disease outcome are also shown.