NLRP3 Inflammasome and MS/EAE

Abstract

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.

Figure 1

Assembly of the NLRP3 inflammasome. (a) Without an activator, NLRP3 is autorepressed by the interaction between LRRs and the NACHT domain. (b) NLRP3 activator opens up NLRP3 and allows to interact with ASC. ASC further interacts with procaspase-1. Although a CARDINAL homolog is not present in mice, we showed human CARDINAL, shown with a shade, as a part of the human NLRP3 inflammasome complex. (c) NLRP3 units polymerize. Active caspase-1 processes maturation of IL-1β and IL-18. Pyroptosis is also induced by activated caspase-1.

Figure 2

Role of NLRP3 inflammasome in the development of the autoimmune responses in EAE. Upon activation by DAMPs and possibly by PAMPs, the NLRP3 inflammasome processes IL-1β and IL-18 maturation in macrophages and DCs, which work as APCs. Secreted IL-1β and IL-18 were detected both by APCs as an autocrine manner and by CD4⁺ T cells, which are being activated with a self-antigen by the APCs. IL-1β and IL-18 induce expression of chemokines and their receptors both by T cells and APCs. Upregulation of chemokines and their receptors enhances migration of T cells and APCs to the CNS to progress EAE.