Inflammasomes are cytosolic sensors that detect pathogens and danger signals in the innate immune system. The NLRP3 inflammasome is currently the most fully characterized inflammasome and is known to detect a wide array of microbes and endogenous damage-associated molecules. Possible involvement of the NLRP3 inflammasome (or inflammasomes) in the development of multiple sclerosis (MS) was suggested in a number of studies. Recent studies showed that the NLRP3 inflammasome exacerbates experimental autoimmune encephalomyelitis (EAE), an animal model of MS, although EAE can also develop without the NLRP3 inflammasome. In this paper, we discuss the NLRP3 inflammasome in MS and EAE development. 1. Inflammasomes Inflammasomes are cytosolic sensors that detect pathogens and stresses in order to mature and secrete proinflammatory cytokines, such as interleukin-1β (IL-1β) and IL-18. Inflammasomes are expressed in phagocytes, such as macrophages and dendritic cells (DCs), and form a multiprotein complex that activates caspase-1. Assembly of inflammasomes that have clear physiological functions in vivo has been reported with relatively few NOD-like receptor (NLR) family members, such as NLRP1, NLRP3 (also called cryopyrin, CIAS1, NALP3), NLRC4 (IRAF), and AIM2 [1]. The NLRP3 inflammasome is currently the most fully characterized inflammasome and is comprised of three different proteins: NLRP3, adapter protein apoptosis-associated speck-like protein (ASC), and procaspase-1. NLRP3 protein is autorepressed by an internal interaction between the NACHT domain and leucine-rich repeats (LRRs) (Figure 1(a)) [2, 3]. Derepression of NLRP3 is essential for the interaction between NLRP3 and ASC through their Pyrin domains (PYD), followed by further interaction between ASC and procaspase-1 through CARD domains (caspase activation and recruitment domains) (Figure 1(b)). Oligomerization of the NLRP3 inflammasome heterotrimer unit leads to procaspase-1 self-cleavage to generate activated caspase-1, which processes maturation of IL-1β and IL-18 and elicits rapid release of those inflammatory cytokines by cell death termed “pyroptosis” (Figure 1(c)). Molecular mechanism by which caspase-1 mediates pyroptosis is still elusive, but is distinguished from apoptosis and necrosis [4, 5]. A molecule termed CARDINAL is known to be involved in the human NLRP3 inflammasome [6] (Figure 1(b)); but its function is unknown and there is no mouse homolog of human CARDINAL. Critical role of CARDINAL in eliciting functions of inflammasomes is questioned, because mouse inflammasomes share basic
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